Androgen receptor modulators and methods for their use

ABSTRACT

Compounds having a structure of Structure I: 
                         
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 6 , Y 1  and Y 2  are as defined herein, and wherein at least one of R 3  or R 4  is a straight-chain C 1 -C 6  haloalkyl, are provided. Uses of such compounds for treatment of various indications, including prostate cancer, as well as methods of treatment involving such compounds are also provided.

STATEMENT OF GOVERNMENT INTEREST

This invention was made in part with government support under Grant No.2R01 CA105304 awarded by the National Cancer Institute. The UnitedStates Government has certain rights in this invention.

BACKGROUND

Technical Field

This invention generally relates to androgen receptor modulators andtheir use for treatment of various indications. In particular theinvention relates to small molecule androgen receptor modulators andtheir use for treatment of various cancers, for example all stages ofprostate cancer, including androgen dependent, androgen-sensitive andcastration-resistant prostate cancers.

Description of the Related Art

Androgens mediate their effects through the androgen receptor (AR).Androgens play a role in a wide range of developmental and physiologicalresponses and are involved in male sexual differentiation, maintenanceof spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A.Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E.Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-36 1(1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K.Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)). Several lines ofevidence show that androgens are associated with the development ofprostate carcinogenesis. Firstly, androgens induce prostaticcarcinogenesis in rodent models (R. L. Noble, Cancer Res 37, 1929-1933(1977); R. L. Noble, Oncology 34, 138-141 (1977)) and men receivingandrogens in the form of anabolic steroids have a higher incidence ofprostate cancer (J. T. Roberts & D. M. Essenhigh, Lancet 2, 742 (1986);J. A. Jackson, J. Waxman & A. M. Spiekerman, Arch Intern Med 149, 2365-236 6 (1989); P. D. Guinan, W. Sadoughi, H. Alsheik, R. J. Ablin, D.Alrenga & I. M. Bush, Am J Surg 131, 599-6 00 (1976)). Secondly,prostate cancer does not develop if humans or dogs are castrated beforepuberty (J. D. Wilson & C. Roehrborn, J Clin Endocrinol Metab 84,4324-4331 (1999); G. Wilding, Cancer Surv 14, 113-130 (1992)).Castration of adult males causes involution of the prostate andapoptosis of prostatic epithelium while eliciting no effect on othermale external genitalia (E. M. Bruckheimer & N. Kyprianou, Cell TissueRes 301, 153-16 2 (2000); J. T. Isaacs, Prostate 5, 545-557 (1984)).This dependency on androgens provides the underlying rationale fortreating prostate cancer with chemical or surgical castration (androgenablation).

Androgens also play a role in female cancers. One example is ovariancancer where elevated levels of androgens are associated with anincreased risk of developing ovarian cancer (K. J. Helzlsouer, A. J.Alberg, G. B. Gordon, C. Longcope, T. L. Bush, S. C. Hoffman & G. W.Comstock, JAMA 274, 1926-1930 (1995); R. J. Edmondson, J. M. Monaghan &B. R. Davies, Br J Cancer 86 , 879-885 (2002)). androgen receptor (AR)has been detected in a majority of ovarian cancers (H. A. Risch, J NatlCancer Inst 90, 1774-1786 (1998); B. R. Rao & B. J. Slotman, Endocr Rev12, 14-26 (1991); G. M. Clinton & W. Hua, Crit Rev Oncol Hematol 25, 1-9(1997)), whereas estrogen receptor-alpha (ERa) and the progesteronereceptor are detected in less than 50% of ovarian tumors.

An effective treatment available for advanced prostate cancer is thewithdrawal of androgens which are essential for the survival of prostateepithelial cells. Androgen ablation therapy causes a temporary reductionin tumor burden concomitant with a decrease in serum prostate-specificantigen (PSA). Unfortunately prostate cancer can eventually grow againin the absence of testicular androgens (castration-resistant disease)(Huber et al 1987 Scand J. Urol Nephrol. 104, 33-39).Castration-resistant prostate cancer is biochemically characterizedbefore the onset of symptoms by a rising titre of serum PSA (Miller etal 1992 J. Urol. 147, 956-96 1). Once the disease becomescastration-resistant most patients succumb to their disease within twoyears.

The androgen receptor (AR) has distinct functional domains that includethe carboxy-terminal ligand-binding domain (LBD), a DNA-binding domain(DBD) comprising two zinc finger motifs, and an N-terminus domain (NTD)that contains one or more transcriptional activation domains. Binding ofandrogen (ligand) to the LBD of androgen receptor (AR) results in itsactivation such that the receptor can effectively bind to its specificDNA consensus site, termed the androgen response element (ARE), on thepromoter and enhancer regions of “normally” androgen regulated genes,such as PSA, to initiate transcription. Androgen receptor (AR) can beactivated in the absence of androgen by stimulation of thecAMP-dependent protein kinase (PKA) pathway, with interleukin-6 (IL-6)and by various growth factors (Culig et al 1994 Cancer Res. 54,5474-5478; Nazareth et al 1996 J. Biol. Chem. 271, 19900-19907; Sadar1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem.277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094).The mechanism of ligand-independent transformation of androgen receptor(AR) has been shown to involve: 1) increased nuclear androgen receptor(AR) protein suggesting nuclear translocation; 2) increased androgenreceptor (AR)/ARE complex formation; and 3) the androgen receptor (AR)-NTD (Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J.Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277,38087-38094). The androgen receptor (AR) may be activated in the absenceof testicular androgens by alternative signal transduction pathways incastration-resistant disease, which is consistent with the finding thatnuclear androgen receptor (AR) protein is present in secondary prostatecancer tumors (Kim et al 2002 Am. J. Pathol. 16 0, 219-226; and van derKwast et al 1991 Inter. J. Cancer 48, 189-193).

Available inhibitors of androgen receptor (AR) include nonsteroidalantiandrogens such as bicalutamide, nilutamide, flutamide, enzalutamide,and investigational drugs ARN-509 and ODM-201, and the steroidalantiandrogen, cyproterone acetate. These antiandrogens target the LBD ofandrogen receptor (AR) and predominantly fail presumably due to pooraffinity and mutations that lead to activation of androgen receptor (AR)by these same antiandrogens (Taplin, M. E., Bubley, G. J., Kom Y. J.,Small E. J., Uptonm M., Rajeshkumarm B., Balkm S. P., Cancer Res., 59,2511-2515 (1999)). These antiandrogens would also have no effect on therecently discovered androgen receptor (AR) splice variants that lack theligand-binding domain (LBD) to result in a constitutively activereceptor which promotes progression of androgen-independent prostatecancer (Dehm S M, Schmidt L J, Heemers H V, Vessella R L, Tindall D J.,Cancer Res 6 8, 546 9-77, 2008; Guo Z, Yang X, Sun F, Jiang R, Linn D E,Chen H, Chen H, Kong X, Melamed J, Tepper C G, Kung H J, Brodie A M,Edwards J, Qiu Y., Cancer Res. 6 9, 2305-13, 2009; Hu et al 2009 CancerRes. 6 9, 16-22; Sun et al 2010 J Clin Invest. 2010 120, 2715-30).

Recent studies developing antagonists to the androgen receptor (AR) haveconcentrated on the C-terminal domain and specifically: 1) theallosteric pocket and AF-2 activity (Estébanez-Perpiñá et al 2007, PNAS104, 16 074-16 079); 2) in silico “drug repurposing” procedure foridentification of nonsteroidal antagonists (Bisson et al 2007, PNAS 104,11927-11932); and coactivator or corepressor interactions (Chang et al2005, Mol Endocrinology 19, 2478-2490; Hur et al 2004, PLoS Biol 2,E274; Estébanez-Perpiñá et al 2005, JBC 280, 806 0-806 8; He et al 2004,Mol Cell 16, 425-438).

The androgen receptor (AR)-NTD is also a target for drug development(e.g. WO 2000/001813), since the NTD contains Activation-Function-1(AF-1) which is the essential region required for AR transcriptionalactivity (Jenster et al 1991. Mol Endocrinol. 5, 1396-404). The AR-NTDimportantly plays a role in activation of androgen receptor (AR) in theabsence of androgens (Sadar, M. D. 1999 J. Biol. Chem. 274, 7777-7783;Sadar M D et al 1999 Endocr Relat Cancer. 6 , 487-502; Ueda et al 2002J. Biol. Chem. 277, 7076-7085; Ueda 2002 J. Biol. Chem. 277,38087-38094; Blaszczyk et al 2004 Clin Cancer Res. 10, 186 0-9; Dehm etal 2006 J Biol Chem. 28, 27882-93; Gregory et al 2004 J Biol Chem. 279,7119-30). The androgen receptor (AR)-NTD is important in hormonalprogression of prostate cancer as shown by application of decoymolecules (Quayle et al 2007, Proc Natl Acad Sci USA. 104,1331-1336).

While the crystal structure has been resolved for the androgen receptor(AR) C-terminus LBD, this has not been the case for the NTD due to itshigh flexibility and intrinsic disorder in solution (Reid et al 2002 J.Biol. Chem. 277, 20079-20086) thereby hampering virtual docking drugdiscovery approaches.

Although progress has been made, there remains a need in the art foradditional and/or improved compounds that modulate androgen receptor(AR). The present disclosure provides these and related advantages.

BRIEF SUMMARY

This invention is based in part on the unexpected discovery that certainSintokamide-related compounds have desirable properties for use asmodulators of androgen receptor (AR). In particular, the compoundsdescribed herein are potent modulators of androgen receptor (AR). Inaccordance with one embodiment, there is provided a compound having astructure of Structure I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein R¹, R², R³, R⁴, R⁵, R⁶, Y¹ and Y² are as defined herein, andwherein at least one of R³ or R⁴ is a straight-chain C₁-C₆haloalkyl.Pharmaceutical compositions comprising a compound of Structure I, apharmaceutically acceptable carrier and an optional additionaltherapeutic agent are also provided.

In other embodiments, the present disclosure provides the use of acompound of Structure I or a composition comprising the same, formodulating androgen receptor (AR) activity. Related methods formodulating androgen receptor (AR) are also provided.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

In the figures, identical reference numbers identify similar elements.The sizes and relative positions of elements in the figures are notnecessarily drawn to scale and some of these elements are arbitrarilyenlarged and positioned to improve figure legibility. Further, theparticular shapes of the elements as drawn are not intended to conveyany information regarding the actual shape of the particular elements,and have been solely selected for ease of recognition in the figures.

FIG. 1 presents R1881 activation data for exemplary compounds andSintokamide A.

FIG. 2 presents comparative data for exemplary compounds and SintokamideA.

FIG. 3 presents comparative data for exemplary compounds and SintokamideB.

DETAILED DESCRIPTION

I. Definitions

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. Thus, the appearances of the phrases “in one embodiment” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment. Furthermore, theparticular features, structures, or characteristics may be combined inany suitable manner in one or more embodiments. Also, as used in thisspecification and the appended claims, the singular forms “a,” “an,” and“the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radical whichis saturated or unsaturated (i.e., contains one or more double and/ortriple bonds), having from one to twenty carbon atoms (e.g., one to ten,or one to six carbon atoms), and which is attached to the rest of themolecule by a single bond. Alkyls comprising any number of carbon atomsfrom 1 to 20 are included. An alkyl comprising up to 6 carbon atoms is aC₁-C₆ alkyl. A C₁-C₆ alkyl includes C₆ alkyls, C₅ alkyls, C₄ alkyls, C₃alkyls, C₂ alkyls and C₁ alkyl (i.e., methyl) and includes, for example,and without limitation, saturated C₁-C₆ alkyl, C₂-C₆ alkenyl (containsat least one carbon-carbon double bond) and C₂-C₆ alkynyl (contains atleast one carbon-carbon triple bond). Non-limiting examples of saturatedC₁-C₆ alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl,n-butyl, i-butyl, sec-butyl, t-butyl and n-pentyl, n-hexyl, and thelike. Non-limiting examples of C₂-C₆ alkenyl include vinyl, allyl,isopropenyl, 1-propene-2-yl, 1-butene-1-yl, 1-butene-2-yl,1-butene-3-yl, 2-butene-1-yl, 2-butene-2-yl, penteneyl, hexeneyl, andthe like. Non-limiting examples of C₂-C₆ alkynyl include ethynyl,propynyl, butynyl, pentynyl, hexynyl, and the like. Unless statedotherwise specifically in the specification, an alkyl group may beoptionally substituted (i.e., a hydrogen atom in the alkyl group may bereplaced with an optional substituent).

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds), andhaving from one to twenty carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, ethenylene, propenylene, n-butenylene,propynylene, n-butynylene, and the like. The alkylene chain is attachedto the rest of the molecule through a single or double bond and to theradical group through a single or double bond. The points of attachmentof the alkylene chain to the rest of the molecule and to the radicalgroup can be through one carbon or any two carbons within the chain.Unless stated otherwise specifically in the specification, an alkylenechain may be optionally substituted.

“Aliphatic carbon” refers to a carbon atom which is not aromatic.

“Alkylaminocarbonyl” refers to a radical of the formula—C(═O)NR_(a)R_(b) where R_(a) and R_(b) are each independently an alkylradical as defined above containing one to twenty carbon atoms. Unlessstated otherwise specifically in the specification, analkylaminocarbonyl group may be optionally substituted.

“Alkylcarbonyl” refers to a radical of the formula —C(═O)R_(a) whereR_(a) is an alkyl radical as defined above containing one to twentycarbon atoms. Unless stated otherwise specifically in the specification,an alkylcarbonyl group may be optionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above containing one to twenty carbon atoms,for example one to six carbon atoms. Unless stated otherwisespecifically in the specification, an alkoxy group may be optionallysubstituted.

“Alkylamino” refers to a radical of the formula —NHR_(a) or —NR_(a)R_(a)where each R_(a) is, independently, an alkyl radical as defined abovecontaining one to twenty carbon atoms. Unless stated otherwisespecifically in the specification, an alkylamino group may be optionallysubstituted.

“Aminocarbonyl” refers to a radical of the formula —C(═O)NH₂. Unlessstated otherwise specifically in the specification, an alkylcarbonylgroup may be optionally substituted.

“Aromatic carbon” refers to a carbon atom which is part of an aromaticring. Aromatic carbons are SP² hybridized and from part of a conjugated,unsaturated ring system having 4n+2 electrons in pi orbitals. Forexample, aromatic carbons may be members on an aryl or heteroaryl ringas defined herein.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems. Aryl radicals include, but are not limited to, arylradicals derived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. Unless statedotherwise specifically in the specification, the term “aryl” or theprefix “ar-” (such as in “aralkyl”) is meant to include aryl radicalsthat are optionally substituted.

“Aralkyl” refers to a radical of the formula -R_(b)-R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. Unless stated otherwise specifically in the specification, anaralkyl group may be optionally substituted.

“Carbocycle” refers to a cyclic structure, wherein the bonds that formthe ring are each carbon-carbon bonds. Carbocycles generally containfrom 3 to 20 carbon atoms within the ring and may be mon, bi ortri-cyclic. Bi and tricyclic carbocycles may be fused (i.e., share twoor more common carbon atoms), spiro (i.e., share one common carbon atom)or linked via a linker atom or atoms. Carbocycles, include cycloalkylsand aryls as defined herein. Unless stated otherwise specifically in thespecification, carbocycle group may be optionally substituted.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,and which is saturated or unsaturated and attached to the rest of themolecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.Unless otherwise stated specifically in the specification, a cycloalkylgroup may be optionally substituted.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br) andiodo (I) substituents.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. A haloalkyl may be straight-chain or branched, and unlessotherwise specified both straight-chain and branched haloalkyls areincluded. A “Chloroalkyl” is a haloalkyl comprising at least one chlorosubstituent. “Perhalo” (e.g., “perchloro”) refers to a carbon atom whichis bound only to other carbon atom(s) and halogen atom(s) (i.e., nohydrogen substituents). Unless stated otherwise specifically in thespecification, a haloalkyl group is optionally substituted.

“Haloalkoxy” refers to an alkoxy radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethoxy, difluoromethoxy, trichloromethoxy,2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy,1,2-dibromoethoxy, and the like. A haloalkoxy may be straight-chain orbranched, and unless otherwise specified both straight-chain andbranched haloalkoxys are included. Unless stated otherwise specificallyin the specification, a haloalkoxy group is optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a stable 3- to18-membered ring radical which consists of two to twelve carbon atomsand from one to six heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. Unless stated otherwise specifically in thespecification, the heterocyclyl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidized; the nitrogen atom maybe optionally quaternized; and the heterocyclyl radical may be partiallyor fully saturated. Examples of such heterocyclyl radicals include, butare not limited to, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless statedotherwise specifically in the specification, a heterocyclyl group may beoptionally substituted. Heterocycles include heteroaryls as definedbelow.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group may be optionallysubstituted.

The term “substituted” used herein means any of the above groups (e.g.,alkyl, haloalkyl, haloalkoxy, alkylene, alkylaminocarbonyl,alkylcarbonyl, alkoxy, alkylamino, aminocarbonyl, cycloalkyl, aryl,aralkyl, carbocycle, deuteroalkyl, haloalkyl, heterocyclyl, and/orheteroaryl) wherein at least one hydrogen atom is replaced by a bond toa non-hydrogen atoms such as, but not limited to: a halogen atom such asF, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups,alkoxy groups, and ester groups; a sulfur atom in groups such as thiolgroups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxidegroups; a nitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,imides, and enamines; a silicon atom in groups such as trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced by a higher-order bond (e.g., a double- ortriple-bond) to a heteroatom such as oxygen in oxo (i.e., C═O),carbonyl, carboxyl, and ester groups; and nitrogen in groups such asimines, oximes, hydrazones, and nitriles. For example, “substituted”includes any of the above groups in which one or more hydrogen atoms arereplaced with —NR_(g)R_(h), —NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h),—NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g),—SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and—SO₂NR_(g)R_(h). “Substituted also means any of the above groups inwhich one or more hydrogen atoms are replaced with —C(═O)R_(g),—C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), —CH₂SO₂NR_(g)R_(h). Inthe foregoing, R_(g) and R_(h) are the same or different andindependently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/orheteroarylalkyl. “Substituted” further means any of the above groups inwhich one or more hydrogen atoms are replaced by a bond to an amino,cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy,alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl group. In addition, each of theforegoing substituents may also be optionally substituted with one ormore of the above substituents.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound. Thus, the term “prodrug” refers to a metabolic precursor of acompound of the invention that is pharmaceutically acceptable. A prodrugmay be active or inactive when administered to a subject in needthereof, but is converted in vivo to an active (or more active)compound. Prodrugs are typically rapidly transformed in vivo to yieldthe parent compound, for example, by hydrolysis in blood. The prodrugcompound often offers advantages of solubility, tissue compatibility ordelayed release in a mammalian organism (see, Bundgard, H., Design ofProdrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion ofprodrugs is provided in Higuchi, T., et al., A.C.S. Symposium Series,Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B.Roche, American Pharmaceutical Association and Pergamon Press, 1987. Thepresent invention is meant to encompass all compounds of structure I,whether acting as a prodrug or the active compound itself, or both.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of Structure (I) beingisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. These radiolabelledcompounds could be useful to help determine or measure the effectivenessof the compounds, by characterizing, for example, the site or mode ofaction, or binding affinity to pharmacologically important site ofaction. Certain isotopically-labelled compounds of Structure (I), forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Substitution with I¹²³ canproduce compounds useful for single photon emission computed tomography(SPECT) imaging. Isotopically-labeled compounds of Structure (I) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in thePreparations and Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising administering a compound of thisinvention to a mammal for a period of time sufficient to yield ametabolic product thereof Such products are typically identified byadministering a radiolabelled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

An “effective amount” refers to a therapeutically effective amount or aprophylactically effective amount. A “therapeutically effective amount”refers to an amount effective, at dosages and for periods of timenecessary, to achieve the desired therapeutic result, such as reducedtumor size, increased life span or increased life expectancy. Atherapeutically effective amount of a compound may vary according tofactors such as the disease state, age, sex, and weight of the subject,and the ability of the compound to elicit a desired response in thesubject. Dosage regimens may be adjusted to provide the optimumtherapeutic response. A therapeutically effective amount is also one inwhich any toxic or detrimental effects of the compound are outweighed bythe therapeutically beneficial effects. A “prophylactically effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired prophylactic result, such assmaller tumors, increased life span, increased life expectancy orprevention of the progression of prostate cancer to CRPC. Typically, aprophylactic dose is used in subjects prior to or at an earlier stage ofdisease, so that a prophylactically effective amount may be less than atherapeutically effective amount.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or

(iv) relieving the symptoms resulting from the disease or condition,i.e., relieving pain without addressing the underlying disease orcondition. As used herein, the terms “disease” and “condition” may beused interchangeably or may be different in that the particular maladyor condition may not have a known causative agent (so that etiology hasnot yet been worked out) and it is therefore not yet recognized as adisease but only as an undesirable condition or syndrome, wherein a moreor less specific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule accompanied by a switch of a singlebond and adjacent double bond. The present invention includes tautomersof any said compounds.

For complex chemical names employed herein, a substituent group is namedbefore the group to which it attaches. For example, cyclopropylethylcomprises an ethyl backbone with cyclopropyl substituent. Except asdescribed below, all bonds are identified in the chemical structurediagrams herein, except for some carbon atoms, which are assumed to bebonded to sufficient hydrogen atoms to complete the valency.

As used herein, the symbol

(hereinafter may be referred to as “a point of attachment bond”) denotesa bond that is a point of attachment between two chemical entities, oneof which is depicted as being attached to the point of attachment bondand the other of which is not depicted as being attached to the point ofattachment bond. For example,

indicates that the chemical entity “XY” is bonded to another chemicalentity via the point of attachment bond. Furthermore, the specific pointof attachment to the non-depicted chemical entity may be specified byinference. For example, the compound CH₃-R³, wherein R³ is H or

infers that when R³ is “XY”, the point of attachment bond is the samebond as the bond by which R³ is depicted as being bonded to CH₃.II. Compounds and Compositions

As noted above, certain embodiments of the present invention aredirected to compounds useful for modulation of androgen receptor (AR).As such, the compounds find utility for treatment of various cancers,including various types of prostate cancers. The compounds describedherein have improved properties relative to other known androgenreceptor (AR) modulators, such as previously known Sintokamidecompounds.

Accordingly, one embodiment of the present invention is directed to acompound having a structure of Structure I:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein:

Y¹ and Y² are each independently O or S;

R¹ is H, C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R² is H, —C(═O)R⁷ or —S(O)_(n)R⁸;

at least one of R³ or R⁴ is a straight-chain C₁-C₆ haloalkyl, and theother one of R³ or R⁴ is C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R⁵ and R⁶ are each independently H, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl or C₁-C₆ haloalkoxy;

R⁷ is C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy;

R⁸ is C₁-C₆ alkyl or C₁-C₆ haloalkyl;

is a carbon-carbon double bond or a carbon-carbon single bond, such thatall valences are satisfied; and

n is 0, 1 or 2.

It is understood that “straight chain haloalkyl” refers to an unbranchedalkyl (e.g. n-propyl, n-butyl, n-pentyl, and the like) comprising atleast one halogen substituent.

All possible stereoisomers are included within the scope of differentembodiments of the invention. Accordingly, in some embodiments thecompound has one of the following structures (Ia), (Ib), (Ic) or (Id):

In some embodiments, the compound has structure (Ia). In some otherembodiments, the compound has structure (Ib). In different embodiments,the compound has structure (Ic). In some more embodiments, the compoundhas structure (Id).

In any of the foregoing embodiments, Y¹ is O. In other embodiments Y² isO. For example, in certain embodiments, both Y¹ and Y² are O.

In some other embodiments, Y¹ is S. In different embodiments Y² is S.For example, in certain embodiments, both Y¹ and Y² are S.

In other embodiments, Y¹ is O and Y² is S. In even more embodiments, Y¹is S and Y² is O.

In some embodiments, R¹ is H. In other embodiments, R¹ is C₁-C₆ alkyl.In other different embodiments, R¹ is C₁-C₆ haloalkyl

In some other of any of the foregoing embodiments, R² is H. For examplein certain embodiments both R¹ and R² are H.

In other of the foregoing embodiments, R² is —C(═O)R⁷. In some of theembodiments, R⁷ is C₁-C₆ alkyl. For example in some embodiments theC₁-C₆ alkyl is saturated and in other embodiments the C₁-C₆ alkyl isunsaturated. In other embodiments, the C₁-C₆ alkyl is unsubstituted, andin different embodiments the C₁-C₆ alkyl is substituted. Specificexamples of various different embodiments of R⁷ C₁-C₆ alkyl moietiesinclude, but are not limited to, ethyl, t-butyl or

In other embodiments, R² is —C(═O)R⁷ and R⁷ is C₁-C₆ alkoxy. Forexample, the C₁-C₆ alkoxy may be substituted or unsubstituted. Invarious specific embodiments, the C₁-C₆ alkoxy is t-butoxy.

In other different embodiments, R² is —C(═O)R⁷ and R⁷ is C₁-C₆haloalkyl. In yet more embodiments, R² is —C(═O)R⁷ and R⁷ is C₁-C₆haloalkoxy.

In different embodiments, R² is —S(O)_(n)R⁸. In some of theseembodiments, R⁸ is C₁-C₆ alkyl. In other embodiments, the C₁-C₆ alkyl isunsubstituted, and in different embodiments the C₁-C₆ alkyl issubstituted. In some more specific embodiments, R⁸ is ethyl. In yetfurther embodiments, n is 2.

In still more embodiments of any of the foregoing compounds, R⁵ is C₁-C₆alkoxy or C₁-C₆ haloalkoxy. In still more embodiments of any of theforegoing compounds, R⁵ is C₁-C₆ alkoxy, such as methoxy. In otherembodiments, R⁶ is H. For example, in some embodiments R⁵ is C₁-C₆alkoxy, such as methoxy, and R⁶ is H. In some other embodiments R⁵ isOH, and R⁶ is H.

In more embodiments of the foregoing, R³ is a straight-chainC₁-C₆haloalkyl, such as 3,3,3-trichloropropyl, and R⁴ is C₁-C₆ alkyl orC₁-C₆haloalkyl. In some of these embodiments, R⁴ is C₁-C₆haloalkyl. Insome other of these embodiments, R⁴ is a branched C₁-C₆ alkyl such as2-methylpropyl. In some other of these embodiments, R⁴ is a branchedC₁-C₆haloalkyl. In other embodiments, R⁴ is a straight-chainC₁-C₆haloalkyl, such as 3,3,3-trichloropropyl.

In more embodiments of the foregoing, R⁴ is a straight-chainC₁-C₆haloalkyl, such as 3,3,3-trichloropropyl, and R³ is C₁-C₆ alkyl orC₁-C₆haloalkyl. In some other of these embodiments, R³ is a branchedC₁-C₆ alkyl such as 2-methylpropyl. In some of these embodiments, R³ isC₁-C₆haloalkyl. In some other of these embodiments, R³ is a branchedC₁-C₆haloalkyl. In other embodiments, R³ is a straight-chainC₁-C₆haloalkyl, such as 3,3,3-trichloropropyl.

In still more embodiments, at least one of R³ or R⁴ is a straight-chainC₁-C₆ chloroalkyl, and the other one of R³ or R⁴ is C₁-C₆ chloroalkyl.For example, in some embodiments the C₁-C₆ chloroalkyl comprises aperchloro-substituted carbon. In even further embodiments, R³ or R⁴, orboth, is 3,3,3-trichloropropyl. In other embodiments, one of R³ or R⁴ is3,3,3-trichloropropyl and the other of R³ or R⁴ is 3,3-dichloropropyl.

In some of any of the foregoing embodiments,

is a carbon-carbon double bond. In other of any of the foregoingembodiments,

is a carbon-carbon single bond.

The compounds described herein are meant to include all racemic mixturesand all individual enantiomers or combinations thereof, whether or notthey are specifically depicted herein. Accordingly, the compoundsinclude racemic mixtures, enantiomers and diastereomers of any of thecompounds described herein. Tautomers of any of the compounds ofStructure I are also included within the scope of the invention.

As noted above, the compounds of the present invention (i.e., compoundsof Structure 1) may contain one or more asymmetric centers. Accordingly,in some embodiments the compounds are mixtures of different enantiomers(e.g., R and S) or different diastereomers. In other embodiments, thecompounds are pure (or enriched) enantiomers or diastereomers. Forpurpose of clarity, the chiral carbons are not always depicted in thecompounds; however, the present invention includes all stereoisomers(pure and mixtures) of all compounds of Structure I.

By way of example, compounds of Structure I contain at least twostereocenters marked with an * below:

Although the compounds are generally depicted as above, the scope of theinvention includes all possible stereoisomers. For example, with respectto Structure I, the invention also includes the following stereoisomers(Ia), (Ib), (Ic) and (Id):

In other particular embodiments of the compounds as described anywhereherein, the following compounds in Table 1 are provided.

TABLE 1 Representative Compounds No. Structure 1-1

1-1a

1-1b

1-1c

1-1d

1-2

1-2a

1-2b

1-2c

1-2d

1-3

1-3a

1-3b

1-3c

1-3d

1-4

1-4a

1-4b

1-4c

1-4d

1-5

1-5a

1-5b

1-5c

1-5d

1-6

1-6a

1-6b

1-6c

1-6d

1-7

1-7a

1-7b

1-7c

1-7d

1-8

1-8a

1-8b

1-8c

1-8d

1-9

1-9a

1-9b

1-9c

1-9d

1-10

1-10a

1-10b

1-10c

1-10d

1-11

1-11a

1-11b

1-11c

1-11d

1-12

1-12a

1-12b

1-12c

1-12d

1-13

1-13a

1-13b

1-13c

1-13d

N/A N/A

Compounds as described herein may be in the free form or in the form ofa salt thereof In some embodiments, compounds as described herein may bein the form of a pharmaceutically acceptable salt, which are known inthe art (Berge et al., J. Pharm. Sci. 1977, 66, 1). Pharmaceuticallyacceptable salt as used herein includes, for example, salts that havethe desired pharmacological activity of the parent compound (salts whichretain the biological effectiveness and/or properties of the parentcompound and which are not biologically and/or otherwise undesirable).Compounds as described herein having one or more functional groupscapable of forming a salt may be, for example, formed as apharmaceutically acceptable salt. Compounds containing one or more basicfunctional groups may be capable of forming a pharmaceuticallyacceptable salt with, for example, a pharmaceutically acceptable organicor inorganic acid. Pharmaceutically acceptable salts may be derivedfrom, for example, and without limitation, acetic acid, adipic acid,alginic acid, aspartic acid, ascorbic acid, benzoic acid,benzenesulfonic acid, butyric acid, cinnamic acid, citric acid,camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid,diethylacetic acid, digluconic acid, dodecylsulfonic acid,ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid,gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid,heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid,hydriodic acid, 2-hydroxyethanesulfonic acid, isonicotinic acid, lacticacid, malic acid, maleic acid, malonic acid, mandelic acid,methanesulfonic acid, 2-napthalenesulfonic acid, naphthalenedisulphonicacid, p-toluenesulfonic acid, nicotinic acid, nitric acid, oxalic acid,pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid,picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid,salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaricacid, thiocyanic acid or undecanoic acid. Compounds containing one ormore acidic functional groups may be capable of forming pharmaceuticallyacceptable salts with a pharmaceutically acceptable base, for example,and without limitation, inorganic bases based on alkaline metals oralkaline earth metals or organic bases such as primary amine compounds,secondary amine compounds, tertiary amine compounds, quaternary aminecompounds, substituted amines, naturally occurring substituted amines,cyclic amines or basic ion-exchange resins. Pharmaceutically acceptablesalts may be derived from, for example, and without limitation, ahydroxide, carbonate, or bicarbonate of a pharmaceutically acceptablemetal cation such as ammonium, sodium, potassium, lithium, calcium,magnesium, iron, zinc, copper, manganese or aluminum, ammonia,benzathine, meglumine, methylamine, dimethylamine, trimethylamine,ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine,tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,glucamine, methylglucamine, theobromine, purines, piperazine,piperidine, procaine, N-ethylpiperidine, theobromine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, morpholine, N-methylmorpholine,N-ethylmorpholine, dicyclohexylamine, dibenzylamine,N,N-dibenzylphenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamineor polyamine resins. In some embodiments, compounds as described hereinmay contain both acidic and basic groups and may be in the form of innersalts or zwitterions, for example, and without limitation, betaines.Salts as described herein may be prepared by conventional processesknown to a person skilled in the art, for example, and withoutlimitation, by reacting the free form with an organic acid or inorganicacid or base, or by anion exchange or cation exchange from other salts.Those skilled in the art will appreciate that preparation of salts mayoccur in situ during isolation and purification of the compounds orpreparation of salts may occur by separately reacting an isolated andpurified compound.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, polymorphs, isomeric forms) as described herein maybe in the solvent addition form, for example, solvates. Solvates containeither stoichiometric or non-stoichiometric amounts of a solvent inphysical association the compound or salt thereof The solvent may be,for example, and without limitation, a pharmaceutically acceptablesolvent. For example, hydrates are formed when the solvent is water oralcoholates are formed when the solvent is an alcohol.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, solvates, isomeric forms) as described herein mayinclude crystalline and amorphous forms, for example, polymorphs,pseudopolymorphs, conformational polymorphs, amorphous forms, or acombination thereof Polymorphs include different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability and/or solubility. Those skilled in the art willappreciate that various factors including recrystallization solvent,rate of crystallization and storage temperature may cause a singlecrystal form to dominate.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, solvates, polymorphs) as described herein includeisomers such as geometrical isomers, optical isomers based on asymmetriccarbon, stereoisomers, tautomers, individual enantiomers, individualdiastereomers, racemates, diastereomeric mixtures and combinationsthereof, and are not limited by the description of the Structureillustrated for the sake of convenience.

The present disclosure also provides a pharmaceutical compositioncomprising any one or more of the compounds (e.g., compounds ofstructure I) disclosed herein and a pharmaceutically acceptable carrier.In some embodiments, the pharmaceutical composition may be for treatingone or more of the following: prostate cancer, breast cancer, ovariancancer, endometrial cancer, bladder cancer, pancreatic cancer,hepatocellular cancer, kidney cancer, liver cancer, salivary glandcarcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarydisease, precocious puberty, spinal and bulbar muscular atrophy, andage-related macular degeneration.

In some embodiments, the pharmaceutical composition is formulated fortopical administration.

In some embodiments, pharmaceutical compositions in accordance with thisinvention may comprise a compound of Structure I, or a salt of such acompound, preferably a pharmaceutically or physiologically acceptablesalt and a pharmaceutically acceptable carrier. Pharmaceuticalpreparations will typically comprise one or more carriers, excipients ordiluents acceptable for the mode of administration of the preparation,be it by injection, inhalation, topical administration, lavage, or othermodes suitable for the selected treatment. Suitable carriers, excipientsor diluents are those known in the art for use in such modes ofadministration.

Suitable pharmaceutical compositions may be formulated by means known inthe art and their mode of administration and dose determined by theskilled practitioner. For parenteral administration, a compound may bedissolved in sterile water or saline or a pharmaceutically acceptablevehicle used for administration of non-water soluble compounds such asthose used for vitamin K. For enteral administration, the compound maybe administered in a tablet, capsule or dissolved in liquid form. Thetablet or capsule may be enteric coated, or in a formulation forsustained release. Many suitable formulations are known, including,polymeric or protein microparticles encapsulating a compound to bereleased, ointments, pastes, gels, hydrogels, or solutions which can beused topically or locally to administer a compound. A sustained releasepatch or implant may be employed to provide release over a prolongedperiod of time. Many techniques known to one of skill in the art aredescribed in Remington: the Science & Practice of Pharmacy by AlfonsoGennaro, 20^(th) ed., Lippencott Williams & Wilkins, (2000).Formulations for parenteral administration may, for example, containexcipients, polyalkylene glycols such as polyethylene glycol, oils ofvegetable origin, or hydrogenated naphthalenes. Biocompatible,biodegradable lactide polymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers may be used to control therelease of the compounds. Other potentially useful parenteral deliverysystems for modulatory compounds include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, andliposomes. Formulations for inhalation may contain excipients, forexample, lactose, or may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may beoily solutions for administration in the form of nasal drops, or as agel.

Compounds for use in the present invention may be obtained from medicalsources or modified using known methodologies from naturally occurringcompounds. In addition, methods of preparing or synthesizing compoundsof the present invention will be understood by a person of skill in theart having reference to known chemical synthesis principles, for examplethe synthetic procedures set forth in PCT Pub. No. WO 2010/020055; whichapplication is hereby incorporated by reference in its entirety for allpurposes.

For example, certain embodiments of the compounds of the presentinvention may be prepared with reference to the following GeneralReaction Scheme I:

General Reaction Scheme I, wherein PG represents a protecting group andall other “R” groups are as defined herein, provides an exemplary methodfor preparation of compounds of structure (I) wherein Y¹ and Y² are O,R⁵ is methoxy and R⁶ is H (i.e., a compound of structure (I′)).Referring to General Reaction Scheme I, appropriate amino acids or aminoacid esters (B and A, respectively) can be purchased or preparedaccording to methods known in the art. In certain embodiments, thesecompounds can be prepared from an appropriate a,b-unsaturated ester asillustrated in the examples. Chiral reagents, such as Ellman'ssulfonamide may be employed to impart the desired stereochemistry of theamino acid (or ester) reagents.

Amide coupling of A and B using standard reagents (e.g., HOAt and EDCI)results in dipeptide C. Dipeptide C is then cyclized by reaction withMeldrum's acid as illustrated in General Reaction Scheme I to yieldcompounds of structure D. PG can optionally be removed and the desiredR² group installed using any number of techniques, including reactionwith an appropriately substituted acyl chloride. Alternatively, PGcorresponds to R² and no further manipulation is required.

It should be noted that General Reaction Scheme I illustrates anembodiment wherein Y¹ and Y² are O, R⁵ is methoxy and R⁶ is H; however,the disclosed compounds are not limited to these embodiments. Otherembodiments may be prepared according to methods analogous to thosedescribed above and in the examples. For example, additional syntheticmodifications may be employed to arrive at different embodiments and/ordifferent starting materials may be employed such that the desiredstructure is obtained without need for further modification. Further,various of the described synthetic procedures may result in a mixture ofstereoisomers (e.g., enantiomers and/or diastereomers). Suchstereoisomers can be separated using known techniques and/orstereospecific or stereoselective reagents and/or methods may beemployed to arrive at the desired stereoisomer.

One skilled in the art will recognize that variations to the order ofthe steps and reagents discussed in reference to the above syntheticschemes are possible. Furthermore, an appropriate protecting groupstrategy, such as those described in, Greene's Protective Groups inOrganic Synthesis, 4^(th)Ed., Peter G. M. Wuts and Theodora W. Greene,John Wiley and Sons, Inc., 2007, which is hereby incorporated byreference in its entirety, may also be employed. In addition, compoundsof structure I having various substitutions (e.g., different values forY¹, Y², R¹, R², R³, R⁴, R⁵, R⁶, etc.) and different positional isomerscan be prepared by modifications to the above starting materials and/orprocedures. Such modifications are well within the ability of one ofordinary skill in the art.

III. Methods

The present compounds find use in any number of methods. For example, insome embodiments the compounds are useful in methods for modulatingandrogen receptor (AR). Accordingly, in one embodiment, the presentdisclosure provides the use of a composition comprising any one of theforegoing compounds of Structure (I) for modulating androgen receptor(AR) activity. For example in some embodiments, modulating androgenreceptor (AR) activity is in a mammalian cell. Modulating androgenreceptor (AR) may be in a subject in need thereof (e.g., a mammaliansubject) and for treatment of any of the described conditions ordiseases.

In other embodiments, modulating androgen receptor (AR) activity is fortreatment of at least one indication selected from the group consistingof: prostate cancer, breast cancer, ovarian cancer, endometrial cancer,bladder cancer, pancreatic cancer, hepatocellular cancer, kidney cancer,liver cancer, salivary gland carcinoma, hair loss, acne, hirsutism,ovarian cysts, polycystic ovary disease, precocious puberty, spinal andbulbar muscular atrophy, and age-related macular degeneration. Forexample in some embodiments, the indication is prostate cancer. In otherembodiments, the prostate cancer is castration resistant prostate cancer(also referred to as hormone refractory, androgen-independent, androgendeprivation resistant, androgen ablation resistant, androgendepletion-independent, castration-recurrent, anti-androgen-recurrent).While in other embodiments, the prostate cancer is androgen-dependentprostate cancer.

In other embodiments, the present disclosure provides a method ofmodulating androgen receptor (AR) activity, the method comprisingadministering a composition comprising any one of the foregoingcompounds of Structure (I), or pharmaceutically acceptable salt,stereoisomer or tautomer thereof to a subject (e.g., mammal) in needthereof

In other further embodiments of the foregoing method, modulatingandrogen receptor (AR) activity is for the treatment of one or more ofthe following: prostate cancer, breast cancer, ovarian cancer,endometrial cancer, bladder cancer, pancreatic cancer, hepatocellularcancer, kidney cancer, liver cancer, salivary gland carcinoma, hairloss, acne, hirsutism, ovarian cysts, polycystic ovary disease,precocious puberty, spinal and bulbar muscular atrophy, and age-relatedmacular degeneration. For example in some embodiments, the prostatecancer is castration resistant prostate cancer (also referred to ashormone refractory, androgen-independent, androgen deprivationresistant, androgen ablation resistant, androgen depletion-independent,castration-recurrent, anti-androgen-recurrent). In other embodiments,the prostate cancer is androgen-dependent prostate cancer.

In accordance with another embodiment, there is provided a use of thecompounds of Structure (I) as described anywhere herein for preparationof a medicament for modulating androgen receptor (AR).

In accordance with a further embodiment, there is provided a method ofscreening for androgen receptor (AR) modulating compounds, wherein thecompounds screened are selected from the compounds as described anywhereherein.

The modulating of the androgen receptor (AR) activity may be in amammalian cell. The modulating of the androgen receptor (AR) activitymay be in a mammal The mammal may be a human.

Alternatively, the administering may be to a mammal The administeringmay be to a mammal in need thereof and in an effective amount for thetreatment of at least one indication selected from the group consistingof: prostate cancer, breast cancer, ovarian cancer, endometrial cancer,bladder cancer, pancreatic cancer, hepatocellular cancer, kidney cancer,liver cancer, salivary gland carcinoma, hair loss, acne, hirsutism,ovarian cysts, polycystic ovary disease, precocious puberty, spinal andbulbar muscular atrophy (e.g., Kennedy's disease), and age-relatedmacular degeneration.

The mammalian cell may be a human cell. The modulating androgen receptor(AR) activity may be for inhibiting androgen receptor (AR) N-terminaldomain activity. The modulating androgen receptor (AR) activity may befor inhibiting androgen receptor (AR) activity. The modulating may be invivo. The modulating androgen receptor (AR) activity may be fortreatment of at least one indication selected from the group consistingof: prostate cancer, breast cancer, ovarian cancer, endometrial cancer,bladder cancer, pancreatic cancer, hepatocellular cancer, kidney cancer,liver cancer, salivary gland carcinoma, hair loss, acne, hirsutism,ovarian cysts, polycystic ovary disease, precocious puberty, spinal andbulbar muscular atrophy (e.g., Kennedy's disease), and age-relatedmacular degeneration. The indication may be prostate cancer. Theprostate cancer may be castration-resistant prostate cancer. Theprostate cancer may be androgen-dependent prostate cancer.

In some embodiments, compounds and all different forms thereof asdescribed herein may be used, for example, and without limitation, incombination with other treatment methods for at least one indicationselected from the group consisting of: prostate cancer, breast cancer,ovarian cancer, endometrial cancer, bladder cancer, pancreatic cancer,hepatocellular cancer, kidney cancer, liver cancer, salivary glandcarcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarydisease, precocious puberty, spinal and bulbar muscular atrophy, andage-related macular degeneration. For example, compounds and all theirdifferent forms as described herein may be used as neoadjuvant (prior),adjunctive (during), and/or adjuvant (after) therapy with surgery,radiation (brachytherapy or external beam), or other therapies (e.g.,HIFU), and in combination with chemotherapies, androgen ablation,antiandrogens or any other therapeutic approach.

With respect to combination therapies, one embodiment of the presentdisclosure provides a combination of any one or more of a compound ofStructure I with one or more currently-used or experimentalpharmacological therapies which are or may be utilized to treat any ofthe above disease states (e.g., castration resistant prostate cancer orKennedy's disease). Methods, uses and pharmaceutical compositionscomprising the above combination are also provided. The compound ofstructure (I) may either be administered together with the additionalpharmacological therapy or the compounds may be administered separately.

In some embodiments, the present invention is directed to a method formodulating androgen receptor (AR) (e.g., for treatment of any of theabove conditions) by administering to a subject in need thereof apharmaceutical composition comprising a compound of structure I and anadditional therapeutic agent. Pharmaceutical compositions (and usesthereof) comprising any one of the foregoing compounds of Formula (I),an additional therapeutic agent and a pharmaceutically acceptablecarrier are also provided. For example, in some embodiments, theadditional therapeutic agent is for treating prostate cancer, breastcancer, ovarian cancer, endometrial cancer, bladder cancer, pancreaticcancer, hepatocellular cancer, kidney cancer, liver cancer, salivarygland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycysticovary disease, precocious puberty, spinal and bulbar muscular atrophy orage-related macular degeneration.

The disclosed compounds, which are thought to interfere with androgenreceptor (AR) principally through binding to the N-terminus domain ofthe androgen receptor (AR), are expected to demonstrate beneficialsynergistic therapeutic effects when used in concert with existingapproved and in-development agents. That is, the biological impact ofusing the agents in concert with one another produces a biological andtherapeutic effect which is greater than the simple additive effect ofeach of them separately.

Accordingly, one embodiment comprises the use of the disclosed compoundsin combination therapy with one or more currently-used or experimentalpharmacological therapies which are utilized for treating the abovedisease states irrespective of the biological mechanism of action ofsuch pharmacological therapies, including without limitationpharmacological therapies which directly or indirectly inhibit theandrogen receptor (AR), pharmacological therapies which are cyto-toxicin nature, and pharmacological therapies which interfere with thebiological production or function of androgen (hereinafter, the “OtherTherapeutic Agents”). By “combination therapy” is meant theadministration of any one or more of a compound of Structure I with oneor more of another therapeutic agent to the same patient such that theirpharmacological effects are contemporaneous with one another, or if notcontemporaneous, that their effects are synergistic with one anothereven though dosed sequentially rather than contemporaneously.

Such administration includes without limitation dosing of one or more ofa compound of Structure I and one or more of the Other TherapeuticAgent(s) as separate agents without any comingling prior to dosing, aswell as formulations which include one or more Other Androgen-BlockingTherapeutic Agents mixed with one or more compound of Structure I as apre-mixed formulation. Administration of the compound(s) of Structure Iin combination with Other Therapeutic Agents for treatment of the abovedisease states also includes dosing by any dosing method includingwithout limitation, topical delivery, intravenous delivery, oraldelivery, intra-peritoneal delivery, intra-muscular delivery, orintra-tumoral delivery.

In another aspect of the present disclosure, the one or more of theOther Therapeutic Agent may be administered to the patient beforeadministration of the compound(s) of Structure I. In another embodiment,the compound(s) of Structure I may be co-administered with one or moreof the Other Therapeutic Agents. In yet another aspect, the one or moreOther Therapeutic Agent may be administered to the patient afteradministration of the compound(s) of Structure I.

It is fully within the scope of the disclosure that the ratio of thedoses of compound(s) of Structure I to that of the one or more OtherTherapeutic Agents may or may not equal to one and may be variedaccordingly to achieve the optimal therapeutic benefit.

For greater clarity the compound(s) of Structure I that are combinedwith the one or more Other Therapeutic Agents for improved treatment ofthe above disease states may comprise, but are not limited to anycompound having a structure of Structure I, including those compoundsshown in Table 1.

The Other Therapeutic Agents include without limitation anypharmacological agent which is currently approved by the FDA in the U.S.(or elsewhere by any other regulatory body) for use as pharmacologicaltreatment of any of the above disease states, or which is currentlybeing used experimentally as part of a clinical trial program thatrelates to the above disease states. Non-limiting examples of the OtherPharmacological Agents comprise, without limitation: the chemical entityknown as enzalutamide(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide)and related compounds, which appears to be a blocker of the androgenreceptor (AR) LBD and is an FDA-approved treatment for prostate cancer;the chemical entity known as Galeterone and related compounds whichappears to be a blocker of the androgen receptor (AR) LBD, and a CYP17lyase inhibitor, and also appears to decrease overall androgen receptor(AR) levels in prostate cancer cells. Galeterone is currently indevelopment as a treatment for prostate cancer; the chemical entityknown as ARN-509 and related compounds which appears to be a blocker ofthe androgen receptor (AR) LBD and is currently in development as atreatment for prostate cancer; the chemical entity known as ODM-201 andrelated compounds, the chemical entity known as abiraterone (or CB-7630;(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol),and related molecules, which appears to block the production of androgenand is an FDA-approved treatment for prostate cancer; the chemicalentity known as bicalutamide(N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide)and related compounds, which appears to be a blocker of the AR LBD andwhich is currently used to treat prostate cancer, the chemical entityknown as nilutamide(5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione)and related compounds, which appears to be a blocker of the androgenreceptor (AR) LBD and which is currently used to treat prostate cancer,the chemical entity known as flutamide(2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide) and relatedcompounds, which appears to be a blocker of the androgen receptor (AR)LBD and which is currently used to treat prostate cancer, the chemicalentities known as cyproterone acetate(6-chloro-1β,2β-dihydro-17-hydroxy-3′H-cyclopropa[1,2]pregna-4,6-diene-3,20-dione)and related compounds, which appears to be a blocker of the androgenreceptor (AR) LBD and which is currently used to treat prostate cancer,the chemical entity known as docetaxel (Taxotere;1,7β,10β-trihydroxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl 4-acetate2-benzoate13-{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate})and related compounds, which appears to be a cytotoxic antimicrotubuleagent and is currently used in combination with prednisone to treatprostate cancer, the chemical entity known as Bevacizumab (Avastin), amonoclonal antibody that recognizes and blocks vascular endothelialgrowth factor A (VEGF-A) and may be used to treat prostate cancer, thechemical entity known as OSU-HDAC42((S)—(+)—N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide), andrelated compounds, which appears to act as a histone deacetylaseinhibitor, and is currently being developed as a treatment for prostatecancer, the chemical entity known as VITAXIN which appears to be amonoclonal antibody against the vascular integrin αvβ3 to preventangiogenesis, and which may be used to treat prostate cancer, thechemical entity known as sunitumib(N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide)and related compounds, which appears to inhibit multiple receptortyrosine kinases (RTKs) and may be used for treatment of prostatecancer, the chemical entity known as ZD-4054(N-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridin-3-sulfonamid)and related compounds, which appears to block the edta receptor andwhich may be used for treatment of prostate cancer, 6 the chemicalentity known as Cabazitaxel (XRP-6258), and related compounds, whichappears to be a cytotoxic microtubule inhibitor, and which is currentlyused to treat prostate cancer; the chemical entity known as MDX-010(Ipilimumab), a fully human monoclonal antibody that binds to and blocksthe activity of CTLA-4 which is currently in development as animmunotherapeutic agent for treatment of prostate cancer; the chemicalentity known as OGX 427 which appears to target HSP27 as an antisenseagent, and which is currently in development for treatment of prostatecancer; the chemical entity known as OGX 011 which appears to targetclusterin as an antisense agent, and which is currently in developmentas a treatment for prostate cancer; the chemical entity known asfinasteride (Proscar, Propecia;N-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide),and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone, and may be used to treatprostate cancer; the chemical entity known as dutasteride (Avodart;5α,17β)-N-{2,5bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide) andrelated molecules, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone, and may be used in thetreatment of prostate cancer; the chemical entity known as turosteride((4aR,4bS,6aS,7S,9aS,9bS,11aR)-1,4a,6a-trimethyl-2-oxo-N-(propan-2-yl)-N-(propan-2ylcarbamoyl)hexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide), andrelated molecules, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and may be used in thetreatment of prostate cancer; the chemical entity known as bexlosteride(LY-191,704;(4aS,10bR)-8-chloro-4-methyl-1,2,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one),and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and may be used in thetreatment of prostate cancer; the chemical entity known as izonsteride(LY-320,236;(4aR,10bR)-8-[(4-ethyl-1,3-benzothiazol-2-yl)sulfanyl]-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one)and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and may be used for thetreatment of prostate cancer; the chemical entity known as FCE 28260 andrelated compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and may be used for thetreatment of prostate cancer; the chemical entity known as SKF105,111,and related compounds, which appears to be a 5-alpha reductase inhibitorthat reduces levels of dihydrotestosterone and may be used for treatmentof prostate cancer. By “related compounds” it is understood that othercompounds having a similar mode of action and/or activity are alsoincluded within the scope of various embodiments. For example, relatedcompounds include other therapeutic agents that have been used fortreatment of prostate cancer, either as a monotherapy or as part of acombination therapy.

Also contemplated in certain embodiments is use of any of the compoundsof structure (I) in combination with inhibitors of: PI3K, BETbromodomains and/or PARP for treatment of the above noted conditions(e.g., prostate cancer). Combinations of the compounds disclosed hereinin combination with Radium 233, which is an FDA approved therapeutic, isalso contemplated for the same purpose.

Accordingly, in certain embodiments the additional therapeutic agent isenzalutamide, Galeterone; ARN-509; ODM-201, abiraterone, bicalutamide,nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab(Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel(XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride,dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260,SKF105,111 Radium 233, predisone or a related compound of any of theforegoing.

In another embodiment, the present disclosure provides the use of anyone of the foregoing pharmaceutical compositions (including compositionscomprising a compound of Structure I and an additional therapeuticagent) for modulating androgen receptor (AR) activity. For example insome embodiments, modulating androgen receptor (AR) activity is in amammalian cell.

In other embodiments, modulating androgen receptor (AR) activity is fortreatment of at least one indication selected from the group consistingof: prostate cancer, breast cancer, ovarian cancer, endometrial cancer,bladder cancer, pancreatic cancer, hepatocellular cancer, kidney cancer,liver cancer, salivary gland carcinoma, hair loss, acne, hirsutism,ovarian cysts, polycystic ovary disease, precocious puberty, spinal andbulbar muscular atrophy, and age-related macular degeneration. Forexample in some embodiments, the indication is prostate cancer. Forexample, in some embodiments, the prostate cancer is castrationresistant prostate cancer, and in other embodiments the prostate canceris androgen-dependent prostate cancer.

In yet another embodiment, the present disclosure provides a method ofmodulating androgen receptor (AR) activity, the method comprisingadministering any one of the foregoing pharmaceutical compositions(including compositions comprising a compound of Structure I and anadditional therapeutic agent) to a subject in need thereof. For examplein some embodiments, modulating androgen receptor (AR) activity is forthe treatment of one or more of the following: prostate cancer, breastcancer, ovarian cancer, endometrial cancer, bladder cancer, pancreaticcancer, hepatocellular cancer, kidney cancer, liver cancer, salivarygland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycysticovary disease, precocious puberty, spinal and bulbar muscular atrophy,and age-related macular degeneration. In still other embodiments, theindication is prostate cancer. For example, in some embodiments, theprostate cancer is castration resistant prostate cancer, while in otherembodiments, the prostate cancer is androgen-dependent prostate cancer.

Compounds as described herein may be administered to a subject. As usedherein, a “subject” may be a human, non-human primate, mammal, rat,mouse, cow, horse, pig, sheep, goat, dog, cat and the like. The subjectmay be suspected of having or at risk for having a cancer, such asprostate cancer, breast cancer, ovarian cancer, salivary glandcarcinoma, bladder cancer, pancreatic cancer, hepatocellular cancer,kidney cancer, liver cancer, or endometrial cancer, or suspected ofhaving or at risk for having acne, hirsutism, alopecia, benign prostatichyperplasia, ovarian cysts, polycystic ovary disease, precociouspuberty, spinal and bulbar muscular atrophy, or age-related maculardegeneration. Diagnostic methods for various cancers, such as prostatecancer, breast cancer, ovarian cancer, salivary gland carcinoma, bladdercancer, pancreatic cancer, hepatocellular cancer, kidney cancer, livercancer, or endometrial cancer, and diagnostic methods for acne,hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts,polycystic ovary disease, precocious puberty, spinal and bulbar muscularatrophy, or age-related macular degeneration and the clinicaldelineation of cancer, such as prostate cancer, breast cancer, ovariancancer, salivary gland carcinoma, bladder cancer, pancreatic cancer,hepatocellular cancer, kidney cancer, liver cancer, or endometrialcancer, diagnoses and the clinical delineation of acne, hirsutism,alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovarydisease, precocious puberty, spinal and bulbar muscular atrophy, orage-related macular degeneration are known to those of ordinary skill inthe art.

Compounds described herein may also be used in assays and for researchpurposes. Definitions used include ligand-dependent activation of theandrogen receptor (AR) by androgens such as dihydrotestosterone (DHT) orthe synthetic androgen (R1881) used for research purposes.Ligand-independent activation of androgen receptor (AR)refers totransactivation of full-length androgen receptor (AR) in the absence ofandrogen (ligand) by, for example, stimulation of the cAMP-dependentprotein kinase (PKA) pathway with forskolin (FSK). Some compounds andcompositions of this invention may inhibit both FSK and androgen (e.g.R1881, a synthetic androgen) induction of ARE-luciferase (ARE-luc).Constitutive activity of androgen receptor (AR) refers to splicevariants lacking androgen receptor (AR) ligand-binding domain. Suchcompounds may block a mechanism that is common to both ligand-dependentand ligand-independent activation of androgen receptor (AR), as well asconstitutively active splice variants of androgen receptor (AR) thatlack ligand-binding domain. This could involve any step in activation ofandrogen receptor (AR) including dissociation of heatshock proteins,essential posttranslational modifications (e.g., acetylation,phosphorylation), nuclear translocation, protein-protein interactions,formation of the transcriptional complex, release of co-repressors,and/or increased degradation. Some compounds and compositions of thisinvention may inhibit ligand-only activity and may interfere with amechanism specific to ligand-dependent activation (e.g., accessibilityof the ligand binding domain (LBD) to androgen). Numerous disorders inaddition to prostate cancer involve the androgen axis (e.g., acne,hirsutism, alopecia, benign prostatic hyperplasia) and compoundsinterfering with this mechanism may be used to treat such conditions.

Compounds or pharmaceutical compositions in accordance with thisinvention or for use in this invention may be administered by means of amedical device or appliance such as an implant, graft, prosthesis,stent, etc. Also, implants may be devised which are intended to containand release such compounds or compositions. An example would be animplant made of a polymeric material adapted to release the compoundover a period of time.

It is to be noted that dosage values may vary with the severity of thecondition to be alleviated. For any particular subject, specific dosageregimens may be adjusted over time according to the individual need andthe professional judgment of the person administering or supervising theadministration of the compositions. Dosage ranges set forth herein areexemplary only and do not limit the dosage ranges that may be selectedby medical practitioners. The amount of active compound(s) in thecomposition may vary according to factors such as the disease state,age, sex, and weight of the subject. Dosage regimens may be adjusted toprovide the optimum therapeutic response. For example, a single bolusmay be administered, several divided doses may be administered over timeor the dose may be proportionally reduced or increased as indicated bythe exigencies of the therapeutic situation. It may be advantageous toformulate parenteral compositions in dosage unit form for ease ofadministration and uniformity of dosage.

The compounds described herein may be used for in vivo or in vitroresearch uses (i.e. non-clinical) to investigate the mechanisms oforphan and nuclear receptors (including steroid receptors such as AR).Furthermore, these compounds may be used individually or as part of akit for in vivo or in vitro research to investigate signal transductionpathways and/or the activation of orphan and nuclear receptors usingrecombinant proteins, cells maintained in culture, and/or animal models.

Various alternative embodiments and examples of the invention aredescribed herein. These embodiments and examples are illustrative andshould not be construed as limiting the scope of the invention. Thefollowing examples are provided for purposes of illustration, notlimitation.

EXAMPLES

All non-aqueous reactions were performed in flame-dried round bottomedflasks. The flasks were fitted with rubber septa and reactions wereconducted under a positive pressure of argon unless otherwise specified.Stainless steel syringes were used to transfer air- andmoisture-sensitive liquids. Flash column chromatography was performed asdescribed by Still et al. (Still, W. C.; Kahn, M.; Mitra, A. J. Org.Chem. 1978, 43, 2923) using 230-400 mesh silica gel. Thin-layerchromatography was performed using aluminium plates pre-coated with 0.25mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254nm). Thin-layer chromatography plates were visualized by exposure toultraviolet light and a “Seebach” staining solution (700 mL water, 10.5g Cerium (IV) sulphate tetrahydrate, 15.0 g molybdato phosphoric acid,17.5 g sulphuric acid) followed by heating (˜1 min) with a heating gun(˜250° C.). Organic solutions were concentrated on Büchi R-114 rotatoryevaporators at reduced pressure (15-30 torr, house vacuum) at 25-40° C.

Commercial regents and solvents were used as received. All solvents usedfor extraction and chromatography were HPLC grade. Normal-phase Si gelSep paks™ were purchased from waters, Inc. Thin-layer chromatographyplates were Kieselgel 60F₂₅₄. All synthetic reagents were purchased fromSigma Aldrich and Fisher Scientific Canada.

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded at 25°C. using a Bruker 400 with inverse probe and Bruker 400 spectrometers,are reported in parts per million on the δ scale, and are referencedfrom the residual protium in the NMR solvent (CDCl₃: δ 7.27 (CHCl₃)).Carbon-13 nuclear magnetic resonance (¹³C NMR) spectra were recordedwith a Bruker 400 spectrometer, are reported in parts per million on theδ scale, and are referenced from the carbon resonances of the solvent(CDCl₃: δ 77.23). Spectral features are tabulated in the followingorder: chemical shift (δ, ppm); multiplicity (s=singlet, d=doublet,t=triplet, m=multiplet, br=broad); coupling constant (J, Hz, number ofprotons).

LNCaP cells were employed for these experiments because they expressendogenous androgen receptor (AR) and secrete prostate-specific antigen(PSA) (Horoszewicz et al 1983 Cancer Res. 43, 1809-1818). LNCaP cellscan be grown either as monolayers in cell culture or as tumors in thewell-characterized xenograft model that progresses to CRPC in castratedhosts (Sato et al 1996 J. Steroid Biochem. Mol. Biol. 58, 139-146;Gleave et al 1991 Cancer Res. 51, 3753-3761; Sato et al 1997 Cancer Res.57, 1584-1589; and Sadar et al 2002 Mol. Cancer Ther. 1(8), 629-637).R1881 (a synthetic androgen) is employed since it is stable and avoidsproblems associated with the labile physiological liganddihydrotestosterone (DHT). A well characterized AR-driven reporter geneconstructs that have been used extensively is the PSA (6.1 kb)enhance/promoter which contains several AREs and is highly inducible byandrogens as well as by FSK and IL 6 (Ueda et al 2002 A J. Biol. Chem.277, 7076-7085).

Example 1 Synthesis of 5,5,5-Trichloro-1-Norvaline Methyl Ester (6)

To a vigorously stirred solution of NaOH (10 g, 0.25 mol) in water (10mL) were successively added BnEt₃N⁺Cl (0.20 g, 0.878 mmol), methylacrylate (1) (4.0 mL, 44.4 mmol), and chloroform (40 g, 500 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 h. Afteraddition of DCM (50 mL) and water (50 mL), the separated organic layerwas washed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. Vacuum distillation of the crude residue gavemethyl 4,4,4-trichlorobutanoate 2 (7.39 g, 36 .0 mmol) as a colourlessliquid in a yield of 81%. The crude residue could also be purified bysilica gel flash chromatography eluting with hexanes/acetone (19:1) toafford 2. by 78° C.-80° C./1 Torr (lit. by 80° C./0.3 Torr); ¹H NMR (300MHz, CDCl₃) δ3.72 (s, 3H), 2.95-3.13 (m, 2H), 2.68-2.86 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ171.6, 98.7, 52.3, 50.0, 31.4; No EI- or ESI-MS weredetected.

To a stirred solution of methyl 4,4,4-trichlorobutanoate 2 (1.35 g, 6.57mmol) in DCM (30 mL) at −78° C. was added DIBAL-H (6.57 mL, 6.57 mmol,1.0 M in hexanes) at a rate of 1.0 mL/min. The reaction mixture wasstirred at −78° C. for 1 h. After successive addition of MeOH (7 mL),HCl (25 mL, 1 M) and Rochelle salt solution (25 mL, 1 M), the reactionmixture was stirred at room temperature for another 1 h. The separatedorganic layer was washed with brine, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo. The crude residue was purified bysilica gel flash chromatography eluting with hexanes/EtOAc (20:1) toafford 4,4,4-trichlorobutanal 3 (1.15 g, 5.78 mmol) as a colourless oilin a yield of 88%. ¹H NMR (400 MHz, CDCl₃) δ9.85 (br. s., 1H), 3.03-3.11(m, 2H), 2.96-3.02 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ198.5, 98.9, 47.5,41.2.

To a stirred solution of aldehyde 3 (1.42 g, 8.09 mmol) in DCM (10 mL)were added (S)-(−)-tert-butanesulfinamide (0.98 g, 6.33 mmol) CuSO₄(3.88 g, 24.2 mmol) at room temperature. The reaction mixture wasstirred at room temperature for 4 days. The catalyst was removed througha pad of Celite® with DCM (200 mL) and the filtrate was concentrated invacuo. The crude residue was purified by silica gel flash chromatographyeluting with hexanes/EtOAc (100:3) to afford (S)-4 (2.0 g, 7.18 mmol) asa colourless oil in a yield of 90%. [α]²⁰ _(D)+171.9° (c 0.68, CHCl₃);¹H NMR (400 MHz, CDCl₃) δ8.14 (br. s., 1H), 3.03-3.15 (m, 2H), 2.93-3.03(m, 2H), 1.18 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 166.0, 98.9, 57.0,50.2, 33.3, 22.5; ESI-MS m/z: 280.2 [M+H]⁺; ESI-HRMS: m/z calcd forC₈H₁₅NO³²S³⁵Cl₃ [M+H]⁺, 277.9940; found, 277.9942.

To a stirred solution of the sulfinimine (S)-4 (1.20 g, 4.31 mmol) inDCM (30 mL) 0° C. were added trimethylsilyl cyanide (1.17 mL, 8.61 mmol)and Sc(OTf)₃ (0.32 g, 0.64 mmol). The reaction mixture was stirred at 0°C. for 2 days and at room temperature for another 2 days. The reactionsolution was ready to recrystallize to furnish pure diastereomericcyanide intermediate (S,S)-5 (1.13 g, 3.69 mmol) in a yield of 20% (86%for both diastereomers). [α]²⁰ _(D)+22.7° (c 0.39, CHCl₃); ¹H NMR (600MHz, CDCl₃) δ4.36 (d, J=6.7 Hz, 1H), 4.15 (br. s., 1H), 2.92 (t, J=7.7Hz, 2H), 2.34-2.47 (m, 2H), 1.28 (s, 9H); ¹³C NMR (150 MHz, CDCl₃)δ118.5, 98.2, 57.6, 50.6, 45.0, 31.7, 22.7; ESI-MS m/z: 329.3 [M+Na]⁺;ESI-HRMS: m/z calcd for C₉H₁₆N₂O³²S³⁵Cl₃ [M+H]⁺, 305.0049; found,305.0051.

HCl gas was generated by dripping HCl (100 mL, conc.) onto anhydrousCaCl₂ granule (100 g). To a stirred solution of (S,S)-5 (579 mg, 1.77mmol) in 10 mL MeOH (10 mL) was bubbled HCl gas for 1 h. The solutionwas stirred at room temperature overnight. Placed in an ice/water bath,the reaction mixture was added saturated NaHCO₃ solution dropwise untilits pH value was adjusted to pH=10. The aqueous layer was extracted withEtOAc (3×30 mL). The combined organic extract was dried over anhydrousMgSO₄, filtered, and evaporated in vacuo. The crude residue was purifiedby silica gel flash chromatography eluting with hexanes/EtOAc (5:1) toafford 6 (300 mg, 1.28 mmol) as a colourless oil in a yield of 73%.[α]²⁰ _(D)+7.0° (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 3.74 (s, 3H),3.50 (dd, J=4.9, 8.2 Hz, 1H), 2.84-2.97 (m, 1H), 2.65-2.84 (m, 1H),2.10-2.30 (m, 1H), 1.87-2.10 (m, 1H), 1.58 (br. s., 2H); ¹³C NMR (100MHz, CDCl₃) δ 175.7, 99.7, 53.4, 52.4, 51.7, 31.6; ESI-MS m/z: 234.3[M+H]⁺; ESI-HRMS: m/z calcd for C₆H₁₁NO₂ ³⁵Cl₃ [M+H]⁺, 233.9855; found,233.9851.

Example 2 Synthesis of N-Boc-5,5,5-Trichloro-d-Norvaline (8)

Treatment of 3 with (R)-Ellman's sulfinamide and anhydrous CuSO₄ yielded(R)-sulfinimine (R)-4 in 93%. An enantioselective Strecker reaction of(R)-4 with TMSCN in the presence of a catalytic amount of Sc(OTf)₃furnished a pair of diastereomers. Diastereomerically pure (R,R)-cyanide(R,R)-5 was obtained from recrystallization in a yield of 25%.

Compound (R,R)-5 (449 mg, 1.46 mmol) was refluxed in HCl (10 mL, 6 M)for 0.5 h. The reaction mixture was cooled to room temperature andwashed with diethyl ether (2×10 mL). The aqueous layer was evaporated at50° C. in vacuo and freeze dried overnight. The yellowish solid 7 wasdirectly used without purification.

To a stirred solution of the crude residue 7 (360 mg, 1.17 mmol) insaturated NaHCO₃ solution (20 mL) was added Boc₂O (254 mg, 1.17 mmol) inTHF (20 mL) at room temperature. The reaction mixture was stirred atroom temperature overnight. Placed in an ice/water bath, the reactionmixture was added 1M HCl dropwise until its pH value was adjusted topH=3. The aqueous suspension was extracted with EtOAc (3×15 mL). Thecombined organic extract was dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The crude residue was purified by silica gelflash chromatography eluting with hexanes/EtOAc (2:1→1:1) to afford 8(300 mg, 0.935 mmol) as a colourless oil in a yield of 80%. [α]²⁰_(D)−24.7° (c 4.7, CHCl₃); ¹H NMR (400 MHz, MeOH-d₄) δ5.09 (br. s., 2H),4.19 (dd, J=4.7, 7.8 Hz, 1H), 2.66-2.91 (m, 2H), 2.21-2.37 (m, 1H),2.01-2.18 (m, 1H), 1.38 (s, 9H); ¹³C NMR (100 MHz, MeOH-d₄) δ174.9,158.0, 100.6, 80.8, 53.6, 52.6, 50.0, 30.1, 28.8; ESI-MS m/z: 320.3[M+H]⁺; ESI-HRMS: m/z calcd for C₁₀H₁₆NO₄NaCl₃ [M+Na]⁺, 342.0043; found,342.0044.

Example 3 Synthesis of 1-1D and 1-1C

To a stirred solution of 6 (89 mg, 0.380 mmol), 8 (122 mg, 0.380 mmol)and HOAt (155 mg, 1.14 mmol) in THF (10 mL) at room temperature wasadded EDCI (218 mg, 1.14 mmol). The reaction mixture was stirred at roomtemperature overnight. After addition of HCl (20 mL, 1 M), the aqueouslayer was extracted with EtOAc (3×20 mL). The combined organic extractwas dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. Thecrude residue was purified by silica gel flash chromatography elutingwith hexanes/EtOAc (6:1→3:1) to afford dipeptide 9 (150 mg, 0.279 mmol)as a light yellow oil in a yield of 73%. [α]²⁰ _(D)+21.9° (c 0.50,CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ6.97 (br. s., 1H), 5.14 (d, J=6.7 Hz,1H), 4.66-4.78 (m, 1H), 4.30 (d, J=2.0 Hz, 1H), 3.81 (s, 3H), 2.72-2.89(m, 3H), 2.63-2.71 (m, 1H), 2.35-2.47 (m, 2H), 2.14-2.21 (m, 1H),2.07-2.13 (m, 1H), 1.48 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ171.8, 171.3,155.9, 99.2, 98.9, 81.2, 53.3, 53.2, 51.3, 51.1, 51.1, 29.6, 29.3, 28.5;ESI-MS m/z: 559.2 [M+Na]⁺; ESI-HRMS: m/z calcd for C₁₆H₂₄N₂O₅NaCl₆[M+Na]⁺, 556.9714; found, 556.9713.

To a stirred solution of dipeptide 9 (150 mg, 0.279 mmol) in H₂O/THF (8mL, 1:1) at 0° C. was added LiOH (0.6 mL, 0.3 mmol, 0.5 M in H₂O). Thereaction mixture was stirred at 0° C. for 1 h then THF was removed invacuo. Placed in an ice/water bath, the reaction mixture was added 1 MHCl dropwise until its pH value was adjusted to pH=3. The aqueous layerwas extracted with EtOAc (3×20 mL). The combined organic extract wasdried over anhydrous MgSO₄, filtered, and concentrated in vacuo. Thecrude residue was used directly for the next step without furtherpurification.

To a stirred solution of the crude carboxylic acid, Meldrum's acid (48.2mg, 0.334 mmol), and DMAP (170.4 mg, 1.39 mmol) in DCM (10 mL) at −10°C. was added IPCC (63 μl, 0.558 mmol) in DCM (100 μl) was added at arate of 10 μl/min. The reaction mixture was stirred −10° C. foradditional 5 h then poured onto KHSO₄ solution (30 mL, 5%). Theseparated aqueous layer was extracted with EtOAc (3×30 mL). The combinedorganic extract was washed with brine, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo. The yellowish crude residue wasrefluxed in MeCN (20 mL) for 3 h then the solvent was removed in vacuo.The crude residue was used directly for the next step without furtherpurification.

To a stirred solution of the crude residue in toluene/MeOH (5 mL, 4:1)at room temperature was dropwise added TMSCHN₂ (0.15 mL, 0.3 mmol, 2.0 Min hexanes). After addition of AcOH (0.15 mL), the reaction mixture wasdried in vacuo. The crude residue was purified by silica gel flashchromatography eluting with hexanes/EtOAc (5:1→3:2) to afford 1-3d and1-3c.

The crude 1-3d was purified through HPLC eluting with MeCN:H₂O (3:1) toyield pure compound 2.5 mg. t_(R)=25.3 min. [α]²⁰ _(D)−14.8° (c 0.27,CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ5.37 (dt, J=3.0, 9.2 Hz, 1H), 5.21 (d,J=8.1 Hz, 1H), 5.18 (s, 1H), 4.75 (d, J=2.0 Hz, 1H), 3.94 (s, 3H),2.93-3.00 (m, 1H), 2.85-2.92 (m, 1H), 2.73 (d, J=9.2 Hz, 2H), 2.45 (br.s., 1H), 2.28-2.39 (m, 2H), 1.86-1.94 (m, 1H), 1.45 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ178.5, 172.4, 169.4, 155.9, 99.5, 99.3, 94.7, 80.6,59.4, 58.3, 53.3, 51.7, 48.4, 29.6, 28.5, 26.0; ESI-MS m/z: 583.2[M+H]⁺; ESI-HRMS: m/z calcd for C₁₈H₂₅N₂O₅ ³⁵Cl₅ ³⁷Cl [M+H]⁺, 560.9865;found, 560.9860.

The crude 1-3c was purified through HPLC eluting with MeCN:H₂O (7:3) toyield pure compound 4.6 mg. t_(R)=38.5 min. [α]²⁰ _(D)+45.4° (c 1.3,CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ5.48 (dt, J=3.5, 8.9 Hz, 1H), 5.30 (d,J=8.7 Hz, 1H), 5.18 (s, 1H), 4.80 (br. s., 1H), 3.94 (s, 3H), 2.95-3.03(m, 1H), 2.78-2.86 (m, 1H), 2.56-2.63 (m, 1H), 2.54 (dd, J=5.8, 9.4 Hz,2H), 2.39-2.44 (m, 1H), 2.33-2.38 (m, 1H), 1.95-2.02 (m, 1H), 1.46 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ178.6, 172.0, 169.0, 155.8, 99.4, 98.9,94.5, 80.4, 59.5, 57.8, 53.6, 51.5, 48.9, 30.9, 28.5, 26.3; ESI-MS m/z:583.2 [M+H]⁺; ESI-HRMS: m/z calcd for C₁₈H₂₅N₂O₅ ³⁵Cl₅ ³⁷Cl [M+H]⁺,560.9865; found, 560.9873.

Compound 1-3d was dissolved in TFA/DCM (3 mL, 25%) and stirred at 0° C.for 1 h then was evaporated in vacuo. After addition of saturated NaHCO₃solution (15 mL), the aqueous layer was extracted with EtOAc (3×15 mL).The combined organic extract was washed with brine, dried over anhydrousMgSO₄, filtered, and concentrated in vacuo. The crude residue waspurified by silica gel flash chromatography eluting with hexanes/EtOAc(9:2→3:2) to afford free amine 1-4d. ESI-MS m/z: 461.0 [M+H]⁺; ESI-HRMS:m/z calcd for C₁₃H₁₇N₂O₃Cl₆ [M+H]⁺, 458.9370; found, 458.9372.

To a stirred solution of the crude free amine 1-4d in THF (2 mL) 0° C.was added propionyl chloride (34 μl, 0.38 mmol) and Et₃N (6 μl, 0.046mmol). The reaction mixture was stirred at room temperature for 3 h.After addition of saturated NaHCO₃ solution (10 mL), the aqueous layerwas extracted with EtOAc (3×10 mL). The combined organic extract waswashed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The crude residue was purified by silica gelflash chromatography eluting with hexanes/EtOAc (7:1→3:2) to afford 1-1d(2.4 mg, 0.0047 mmol) as a colourless solid in a yield of 1.7%. [α]²⁰_(D)−28.3° (c 0.53, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ6.22 (d, J=8.7 Hz,1H), 5.70 (td, J=3.6, 9.0 Hz, 1H), 5.19 (s, 1H), 4.75 (dd, J=3.1, 5.6Hz, 1H), 3.95 (s, 3H), 2.93-3.01 (m, 1H), 2.75-2.84 (m, 1H), 2.63-2.72(m, 2H), 2.43-2.51 (m, 1H), 2.33-2.40 (m, 2H), 2.28 (qd, J=3.3, 7.6 Hz,2H), 1.91-1.99 (m, 1H), 1.17 (t, J=7.7 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃)δ178.6, 174.1, 171.7, 169.3, 99.5, 99.2, 94.7, 59.4, 58.3, 51.7, 51.6,48.4, 30.2, 29.8, 26.1, 9.9; ESI-MS m/z: 539.2 [M+Na]⁺; ESI-HRMS: m/zcalcd for C₁₆H₂₁N₂O₄ ³⁵Cl₅ ³⁷Cl [M+H]⁺, 516.9603; found, 516.9608.

Compound 1-3c was dissolved in TFA/DCM (3 mL, 25%) and stirred at 0° C.for 1 h then was evaporated in vacuo. After addition of saturated NaHCO₃solution (15 mL), the aqueous layer was extracted with EtOAc (3×15 mL).The combined organic extract was washed with brine, dried over anhydrousMgSO₄, filtered, and concentrated in vacuo. The crude residue waspurified by silica gel flash chromatography eluting with hexanes/EtOAc(9:2→1:2) to afford free amine 1-4c. ¹H NMR (600 MHz, CDCl₃) δ5.14 (s,1H), 4.29 (t, J=5.0 Hz, 1H), 3.88 (s, 3H), 2.78 (ddd, J=4.3, 11.4, 14.2Hz, 1H), 2.54-2.63 (m, 1H), 2.23-2.31 (m, 1H), 2.13-2.22 (m, 1H), 1.75(br. s., 4H); ESI-MS m/z: 461.0 [M+H]⁺; ESI-HRMS: m/z calcd forC₁₃H₁₇N₂O₃Cl₆ [M+H]⁺, 458.9370; found, 458.9381.

To a stirred solution of the crude free amine 1-4c in THF (2 mL) 0° C.was added propionyl chloride (34 μl, 0.38 mmol) and Et₃N (6 μl, 0.046mmol). The reaction mixture was stirred at room temperature for 3 h.After addition of saturated NaHCO₃ solution (10 mL), the aqueous layerwas extracted with EtOAc (3×10 mL). The combined organic extract waswashed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The crude residue was purified by silica gelflash chromatography eluting with hexanes/EtOAc (3:2→1:1) to afford 1-1c(3.0 mg, 0.0058 mmol) as a colourless solid in a yield of 2.1%. [α]²⁰_(D)+27.6° (c 0.65, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ6.28 (d, J=8.2 Hz,1H), 5.79 (td, J=3.6, 8.4 Hz, 1H), 5.19 (s, 1H), 4.79 (m, 1H), 3.95 (s,3H), 2.98 (ddd, J=4.6, 11.8, 14.3 Hz, 1H), 2.71-2.79 (m, 1H), 2.57-2.63(m, 1H), 2.54 (dd, J=6.1, 9.2 Hz, 2H), 2.42-2.49 (m, 1H), 2.34-2.41 (m,1H), 2.30 (qd, J=3.8, 7.6 Hz, 2H), 1.99-2.08 (m, 1H), 1.19 (t, J=7.7 Hz,3H); ¹³C NMR (150 MHz, CDCl₃) δ178.6, 174.0, 171.7, 168.9, 99.3, 98.9,94.5, 59.5, 57.9, 51.9, 51.4, 48.9, 31.1, 29.9, 26.3, 9.9; ESI-MS m/z:539.2 [M+Na]⁺; ESI-HRMS: m/z calcd for C₁₆H₂₁N₂O₄ ³⁵Cl₅ ³⁷Cl [M+H]⁺,516.9603; found, 516.9598.

Example 4 Synthesis of 1-5D

To a stirred solution of the crude free amine 1-4d (6 mg, 0.013 mmol) inTHF (2 mL) 0° C. was added pivaloyl chloride (34 μl, 0.38 mmol) and Et₃N(6 μl, 0.046 mmol). The reaction mixture was stirred at room temperaturefor 3 h. After addition of saturated NaHCO₃ solution (10 mL), theaqueous layer was extracted with EtOAc (3×10 mL). The combined organicextract was washed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The crude residue was purified by silica gelflash chromatography eluting with hexanes/EtOAc (25:2→5:1) to afford1-5d (2.2 mg, 0.0040 mmol) as a colourless solid in a yield of 31%.[α]²⁰ _(D)−17.3° (c 0.23, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ6.41 (d,J=7.9 Hz, 1H), 5.60 (dt, J=3.4, 8.7 Hz, 1H), 5.18 (s, 1H), 4.76 (dd,J=3.2, 5.1 Hz, 1H), 3.94 (s, 3H), 2.96 (ddd, J=4.9, 11.4, 14.4 Hz, 1H),2.76 (ddd, J=3.5, 11.5, 14.6 Hz, 1H), 2.65-2.73 (m, 2H), 2.43-2.50 (m,1H), 2.37-2.43 (m, 1H), 2.29-2.37 (m, 1H), 1.94-2.03 (m, 1H), 1.23 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ178.9, 178.5, 171.8, 169.3, 99.5, 99.2,94.6, 59.4, 58.3, 51.9, 51.7, 48.4, 39.0, 29.9, 27.7, 26.0; ESI-MS m/z:567.0 [M+Na]⁺; ESI-HRMS: m/z calcd for C₁₈H₂₄N₂O₄NaCl₆ [M+Na]⁺,564.9765; found, 564.9756.

Example 5 Preparation of Compound (R)-4

Under a similar procedure described in Example 1, (R)-4 (2.92 g, 10.5mmol) was prepared from 3 (2.0 g, 11.3 mmol) as a colourless oil in ayield of 93%. The crude residue was purified by silica gel flashchromatography eluting with hexanes/EtOAc (36:1). [α]²⁰ _(D)−162.3° (c1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ8.16 (br. s., 1H), 3.05-3.17 (m,2H), 2.98-3.04 (m, 2H), 1.19 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ166.0,99.0, 57.0, 50.3, 33.3, 22.5; ESI-MS m/z: 280.3 [M+H]⁺; ESI-HRMS: m/zcalcd for C₈H₁₅NO³²S³⁵Cl₃ [M+H]⁺, 277.9940; found, 277.9938.

Example 6 Preparation of Compound (R,R)-5

Under a similar procedure described in Example 1, (R,R)-5 (2.27 g, 7.42mmol) was prepared from (R)-4 (2.50 g, 8.97 mmol) as a colourless oil ina yield of 25% (83% for both diastereomers). [α]²⁰ _(D)−28.0° (c 0.4,CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ4.36 (br. s., 1H), 4.16 (br. s., 1H),2.92 (t, J=7.6 Hz, 2H), 2.28-2.52 (m, 2H), 1.28 (s, 9H); ¹³C NMR (100MHz, CDCl₃) δ118.5, 98.2, 57.8, 50.6, 45.2, 31.7, 22.8; ESI-MS m/z:329.3 [M+Na]⁺; ESI-HRMS: m/z calcd for C₉H₁₆N₂O³²S³⁵Cl₃ [M+H]⁺,305.0049; found, 305.0056.

Example 7 Preparation of 1-7C and 1-7D

11 (196 mg, 0.436 mmol) was prepared from 10 (140 mg, 0.770 mmol) and 8(165 mg, 0.514 mmol) as illustrated above and isolated as a colourlessoil in a yield of 85%. The crude residue was purified by silica gelflash chromatography eluting with hexanes/EtOAc (5:1→3:1). [α]²⁰_(D)+6.4° (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ6.90 and 6.82 (br. s.each, 1H), 5.35 and 5.25 (d each, J=5.5 Hz and 7.9 Hz each, 1H), 4.60(td, J=4.4, 8.8 Hz, 1H), 4.32 (br. s., 1H), 3.72 (s, 3H), 2.67-2.85 (m,2H), 2.29-2.41 (m, 1H), 2.01-2.15 (m, 1H), 1.59-1.70 (m, 2H), 1.52-1.59(m, 1H), 1.45 (s, 9H), 0.87-0.97 (m, 6H); ¹³C NMR (100 MHz, CDCl₃)δ173.4, 171.2, 155.9, 99.4, 80.7, 52.6, 51.2, 50.9, 41.5, 41.4, 29.7,28.5, 25.1, 23.0, 21.9; ESI-MS m/z: 471.3 [M+Na]⁺; ESI-HRMS: m/z calcdfor C₁₇H₂₉N₂O₅Na³⁵Cl₃ [M+Na]⁺, 469.1040; found, 469.1044.

1-7d (2.5 mg, 0.0058 mmol) was prepared from 11 (100 mg, 0.223 mmol) asa colourless oil. The crude residue was purified by silica gel flashchromatography eluting with hexanes/EtOAc (5:1→3:2). The yield from1-13d was 72%. [α]²⁰ _(D)−76.0° (c 0.5, CHCl₃); ¹H NMR (600 MHz, CDCl₃)δ6.30 (d, J=8.7 Hz, 1H), 5.74 (td, J=3.1, 9.0 Hz, 1H), 5.09 (s, 1H),4.60 (t, J=5.1 Hz, 1H), 3.89 (s, 3H), 2.98 (ddd, J=4.6, 11.6, 14.5 Hz,1H), 2.73-2.80 (m, 1H), 2.32-2.39 (m, 1H), 2.29 (q, J=7.5 Hz, 2H),1.88-1.95 (m, 1H), 1.82-1.85 (m, 2H), 1.74-1.80 (m, 1H), 1.18 (t, J=7.4Hz, 3H), 0.94 (d, J=6.1 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H); ¹³C NMR (150MHz, CDCl₃) δ181.3, 173.8, 171.3, 169.8, 99.6, 93.6, 59.0, 59.0, 51.6,51.5, 39.2, 30.6, 29.9, 24.4, 23.9, 22.7, 10.0; ESI-MS m/z: 451.2[M+Na]⁺; ESI-HRMS: m/z calcd for C₁₇H₂₆N₂O₄Cl₃ [M+H]⁺, 427.0958; found,427.0961.

1-7c (3.9 mg, 0.00914 mmol) was prepared from 1-13c (8.5 mg, 0.0228mmol) as a colourless oil in a yield of 40%. The crude residue waspurified by silica gel flash chromatography eluting with hexanes/EtOAc(3:2→1:1). [α]²⁰ _(D)+47.5° (c 0.4, CHCl₃); ¹H NMR (600 MHz, CDCl₃)δ6.33 (d, J=8.2 Hz, 1H), 5.77 (td, J=3.3, 8.6 Hz, 1H), 5.09 (s, 1H),4.66 (dd, J=3.1, 6.7 Hz, 1H), 3.89 (s, 3H), 2.99 (ddd, J=4.4, 12.0, 14.3Hz, 1H), 2.71-2.78 (m, 1H), 2.46 (tt, J=4.2, 12.7 Hz, 1H), 2.29 (qd,J=3.8, 7.6 Hz, 2H), 1.95-2.03 (m, J=3.8, 9.0, 12.5, 12.5 Hz, 1H),1.80-1.85 (m, 1H), 1.73-1.80 (m, 2H), 1.18 (t, J=7.7 Hz, 3H), 0.94 (d,J=5.6 Hz, 3H), 0.91 (d, J=6.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ181.2,173.9, 171.3, 169.5, 99.5, 93.5, 59.1, 58.6, 51.8, 51.5, 39.4, 31.0,29.9, 24.5, 24.0, 22.8, 10.0; ESI-MS m/z: 451.2 [M+Na]⁺; ESI-HRMS: m/zcalcd for C₁₇H₂₅N₂O₄NaCl₃ [M+Na]⁺, 449.0778; found, 449.0775.

Example 8 Preparation of 1-8C and 1-8D

13 (82 mg, 0.183 mmol) was prepared from 6 (52 mg, 0.221 mmol) and 11(80 mg, 0.350 mmol) as a colourless oil in a yield of 82%. The cruderesidue was purified by silica gel flash chromatography eluting withhexanes/EtOAc (6:1→3:1). [α]²⁰ _(D)+36.1° (c 0.8, CHCl₃); ¹H NMR (400MHz, CDCl₃) δ7.04 and 6.93 (br. s.each, 1H), 5.01 (br. s., 1H), 4.69(td, J=4.9, 7.9 Hz, 1H), 4.16 (br. s., 1H), 3.77 (s, 3H), 2.73-2.82 (m,1H), 2.61-2.71 (m, 1H), 2.32-2.43 (m, 1H), 2.06-2.17 (m, 1H), 1.61-1.72(m, 2H), 1.47-1.53 (m, 1H), 1.43 (s, 9H), 0.90-0.95 (m, 6H); ¹³C NMR(100 MHz, CDCl₃) δ172.9, 171.9, 155.9, 99.1, 80.4, 53.3, 52.9, 51.1,50.9, 41.0, 29.7, 28.5, 25.0, 23.1, 22.3; ESI-MS m/z: 469.2 [M+Na]⁺;ESI-HRMS: m/z calcd for C₁₇H₃₀N₂O₅ ³⁵Cl₃ [M+H]⁺, 447.1220; found,447.1231.

1-8d (4.0 mg, 0.0093 mmol) was prepared from 13 (79.2 mg, 0.176 mmol) asa colourless oil. The crude residue was purified by silica gel flashchromatography eluting with hexanes/EtOAc (5:1→3:2). The yield from1-12d was 23%. [α]²⁰ _(D)−25.0° (c 0.4, CHCl₃); ¹H NMR (600 MHz, CDCl₃)δ5.97 (d, J=7.7 Hz, 1H), 5.70 (ddd, J=3.1, 8.4, 11.0 Hz, 1H), 5.15 (s,1H), 4.72 (dd, J=3.1, 5.6 Hz, 1H), 3.92 (s, 3H), 2.76 (ddd, J=4.4, 11.9,14.0 Hz, 1H), 2.65-2.72 (m, 1H), 2.43 (ddd, J=3.8, 11.6, 14.2 Hz, 1H),2.28-2.35 (m, 1H), 2.24 (qd, J=4.1, 7.5 Hz, 2H), 1.69-1.76 (m, 1H),1.60-1.63 (m, 1H), 1.41-1.46 (m, 1H), 1.15 (t, J=7.7 Hz, 3H), 1.04 (d,J=6.7 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ178.2,173.8, 173.7, 169.1, 99.4, 94.7, 59.3, 58.3, 51.7, 48.2, 41.0, 29.7,26.0, 25.2, 23.8, 21.4, 9.9; ESI-MS m/z: 451.3 [M+Na]⁺; ESI-HRMS: m/zcalcd for C₁₇H₂₅N₂O₄NaCl₃ [M+Na]⁺, 449.0778; found, 449.0780.

1-8c (1.3 mg, 0.003 mmol) was prepared from 1-12c (8.0 mg, 0.0215 mmol)as a colourless oil in a yield of 14%. The crude residue was purified bysilica gel flash chromatography eluting with hexanes/EtOAc (3:2→1:1).[α]²⁰ _(D)+60.0° (c 0.33, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ5.96 (br. s.,1H), 5.78 (t, J=8.4 Hz, 1H), 5.15 (s, 1H), 4.77 (dd, J=3.3, 5.4 Hz, 1H),3.92 (s, 3H), 2.55-2.62 (m, 1H), 2.50 (dd, J=6.7, 9.2 Hz, 2H), 2.30-2.36(m, 1H), 2.27 (qd, J=2.3, 7.6 Hz, 2H), 1.71-1.77 (m, 1H), 1.65 (ddd,J=3.1, 10.2, 13.3 Hz, 1H), 1.44-1.50 (m, 1H), 1.17 (t, J=7.4 Hz, 3H),1.07 (d, J=6.7 Hz, 3H), 0.95 (d, J=6.7 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃)δ178.3, 173.9, 173.5, 168.9, 99.0, 94.6, 59.4, 57.8, 51.9, 48.8, 42.1,29.8, 26.1, 25.4, 23.8, 21.3, 9.9; ESI-MS m/z: 451.3 [M+Na]⁺; ESI-HRMS:m/z calcd for C₁₇H₂₅N₂O₄NaCl₃ [M+Na]⁺, 449.0778; found, 449.0781.

Example 9 Preparation of 1-1A and 1-1B

Compound (S,S)-5 (258 mg, 0.844 mmol) was refluxed in HCl (10 mL, 6 M)for 0.5 h. The reaction mixture was cooled to room temperature andwashed with diethyl ether (2×10 mL). The aqueous layer was evaporated at50° C. in vacuo and freeze dried overnight. The yellowish solid was usedwithout purification.

To a stirred solution of the solid in saturated NaHCO₃ solution (20 mL)was added Boc₂O (184 mg, 0.844 mmol) in THF (20 mL) at room temperature.The reaction mixture was stirred at room temperature overnight. Placedin an ice/water bath, the reaction mixture was added 1M HCl dropwiseuntil its pH value was adjusted to pH=3. The aqueous suspension wasextracted with EtOAc (3×15 mL). The combined organic extract was driedover anhydrous MgSO₄, filtered, and concentrated in vacuo. The cruderesidue was purified by silica gel flash chromatography eluting withhexanes/EtOAc (2:1→1:1) to afford 14 (186 mg, 0.575 mmol) as acolourless oil in a yield of 68%. [α]²⁰ _(D)+26.1° (c 1.8, CHCl₃); ¹HNMR (400 MHz, MeOH-d₄) δ5.09 (br. s., 2H), 4.19 (dd, J=4.7, 7.8 Hz, 1H),2.66-2.91 (m, 2H), 2.21-2.37 (m, 1H), 2.01-2.18 (m, 1H), 1.38 (s, 9H);¹³C NMR (100 MHz, MeOH-d₄) δ174.9, 158.0, 100.6, 80.8, 53.6, 52.6, 50.0,30.1, 28.8; ESI-MS m/z: 320.3 [M+H]⁺; ESI-HRMS: m/z calcd forC₁₀H₁₆NO₄NaCl₃ [M+Na]⁺, 342.0043; found, 342.0044.

Methanolysis of Strecker product 15 afforded racemic5,5,5-trichloronorvaline methyl ester 16 in a yield of 83% according tothe above scheme.

Under a similar procedure to that described above, 17 (70 mg, 0.130mmol) was prepared from 16 (36 mg, 0.153 mmol) and 14 (49 mg, 0.153mmol) as a colourless oil in a yield of 85%. The crude residue waspurified by silica gel flash chromatography eluting with hexanes/EtOAc(6:1→3:1). [α]²⁰ _(D)+3.3° (c 1.2, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ6.85 (d, J=6.1 Hz, 1H), 5.11 (d, J=7.2 Hz, 1H), 4.72 (td, J=5.1, 7.9 Hz,1H), 4.22 (d, J=6.1 Hz, 1H), 3.81 (s, 3H), 2.74-2.85 (m, 3H), 2.64-2.72(m, 1H), 2.40-2.47 (m, 1H), 2.32-2.38 (m, 1H), 2.07-2.20 (m, 2H), 1.46(s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ171.7, 171.2, 155.9, 99.2, 99.0,81.2, 53.4, 53.2, 51.3, 51.2, 51.0, 29.7, 29.1, 28.5; ESI-MS m/z: 559.2[M+Na]⁺; ESI-HRMS: m/z calcd for C₁₆H₂₄N₂O₅NaCl₆ [M+Na]⁺, 556.9714;found, 556.9713.

Under a similar procedure described above, 1-1a (3.8 mg, 0.0073 mmol)was prepared from 19 (60.8 mg, 0.113 mmol) as a colourless oil. Thecrude residue was purified by silica gel flash chromatography elutingwith hexanes/EtOAc (5:1→3:2). The yield from 1-3a was 60%. [α]²⁰_(D)+50.0° (c 0.16, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ6.21 (d, J=8.2 Hz,1H), 5.70 (td, J=3.6, 9.0 Hz, 1H), 5.19 (s, 1H), 4.75 (dd, J=3.3, 5.4Hz, 1H), 3.94 (s, 3H), 2.94-3.01 (m, 1H), 2.76-2.82 (m, 1H), 2.64-2.72(m, 2H), 2.43-2.50 (m, 1H), 2.33-2.40 (m, 2H), 2.28 (qd, J=3.6, 7.7 Hz,2H), 1.91-1.99 (m, 1H), 1.17 (t, J=7.7 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃)δ178.6, 174.0, 171.7, 169.3, 99.5, 99.2, 94.7, 59.4, 58.3, 51.7, 51.6,48.4, 30.2, 29.8, 26.1, 9.9; ESI-MS m/z: 539.1 [M+Na]⁺; ESI-HRMS: m/zcalcd for C₁₆H₂₀N₂O₄Na³⁵Cl₆ [M+Na]⁺, 536.9453; found, 536.9441.

Under a similar procedure described above, 1-1b (2.2 mg, 0.0042 mmol)was prepared from 1-3b (8.9 mg, 0.0193 mmol) as a colourless oil in ayield of 22%. The crude residue was purified by silica gel flashchromatography eluting with hexanes/EtOAc (3:2→1:1). [α]²⁰ _(D)−56.0° (c0.25, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ6.27 (d, J=8.7 Hz, 1H), 5.79 (td,J=3.6, 8.7 Hz, 1H), 5.19 (s, 1H), 4.79 (m, 1H), 3.95 (s, 3H), 2.98 (ddd,J=4.6, 11.8, 14.3 Hz, 1H), 2.75 (ddd, J=3.6, 12.3, 14.3 Hz, 1H),2.57-2.63 (m, 1H), 2.54 (dd, J=6.1, 8.7 Hz, 2H), 2.46 (tt, J=4.2, 12.7Hz, 1H), 2.35-2.41 (m, 1H), 2.30 (qd, J=3.8, 7.6 Hz, 2H), 2.00-2.08 (m,1H), 1.19 (t, J=7.4 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ178.6, 174.0,171.7, 168.9, 99.3, 98.9, 94.5, 59.5, 57.9, 51.9, 51.4, 48.9, 31.1,29.9, 26.3, 9.9; ESI-MS m/z: 539.1 [M+Na]⁺; ESI-HRMS: m/z calcd forC₁₆H₂₀N₂O₄Na₃₅Cl₆ [M+Na]⁺, 536.9452; found, 536.9456.

Example 10 Preparation of 1-9C

1-9c (1.6 mg, 0.0035 mmol) was prepared from free amine analogue of1-13c (6.0 mg, 0.0161 mmol) and pentynoyl chloride, and isolated as acolourless oil in a yield of 21%. The crude residue was purified bysilica gel flash chromatography eluting with hexanes/EtOAc (5:1→2:1);[α]²⁰ _(D)+50.0° (c 0.14, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 6.50 (d,J=8.1 Hz, 1H), 5.80 (dt, J=3.3, 8.5 Hz, 1H), 5.10 (s, 1H), 4.66 (dd,J=3.07, 6.66 Hz, 1H), 3.89 (s, 3H), 2.97-3.04 (m, 1H), 2.75-2.83 (m,1H), 2.56-2.64 (m, 1H), 2.50-2.55 (m, 1H), 2.44-2.50 (m, 3H), 2.02-2.05(m, 1H), 1.96-2.02 (m, 1H), 1.80-1.87 (m, 1H), 1.72-1.80 (m, 2H), 0.94(d, J=6.1 Hz, 3H), 0.91 (d, J=6.1 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃)δ181.2, 171.0, 170.9, 169.5, 99.5, 93.5, 83.0, 69.8, 59.1, 58.6, 52.0,51.4, 39.3, 35.6, 31.0, 24.5, 24.0, 22.8, 15.2. ESI-MS m/z: 475.2[M+Na]⁺; ESI-HRMS: m/z calcd for C₁₉H₂₅N₂O₄NaCl₃ [M+Na]⁺, 473.0778;found, 473.0781.

Example 11 Preparation of 1-2D

1-2d (1.6 mg, 0.0035 mmol) was prepared from 1-4d (5 mg, 0.0108 mmol)and pentynoyl chloride as a colourless oil in a yield of 39%. The cruderesidue was purified by silica gel flash chromatography eluting withhexanes/EtOAc (10:1→5:1). [α]²⁰ _(D)−30.0° (c 0.2, CHCl₃); ¹H NMR (600MHz, CDCl₃) δ6.41 (d, J=8.6 Hz, 1H), 5.74 (dt, J=3.2, 8.9 Hz, 1H), 5.19(s, 1H), 4.70-4.79 (m, 1H), 3.95 (s, 3H), 2.95-3.02 (m, 1H), 2.81-2.88(m, 1H), 2.64-2.72 (m, 2H), 2.55-2.63 (m, 1H), 2.51-2.55 (m, 1H),2.44-2.51 (m, 3H), 2.33-2.42 (m, 2H), 2.03 (t, J=2.5 Hz, 1H), 1.93-2.00(m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ178.6, 171.4, 171.1, 169.2, 99.5,99.2, 94.6, 83.0, 69.9, 59.4, 58.4, 51.8, 51.6, 48.5, 35.6, 30.2, 26.2,15.1; ESI-MS m/z: 562.9 [M+Na]⁺; ESI-HRMS: m/z calcd forC₁₈H₂₀N₂O₄Na³⁵Cl₅ ³⁷Cl [M+Na]⁺, 562.9422; found, 562.9424.

Example 12 Preparation of 1-2C

1-2c (1.6 mg, 0.0035 mmol) was prepared from 1-4c (5 mg, 0.0108 mmol)and pentynoyl chloride as a colourless oil in a yield of 37%. The cruderesidue was purified by silica gel flash chromatography eluting withhexanes/EtOAc (5:1→2:1). [α]²⁰ _(D)+25.9° (c 0.27, CHCl₃); ¹H NMR (600MHz, CDCl₃) δ6.47 (d, J=8.3 Hz, 1H), 5.83 (dt, J=3.6, 8.4 Hz, 1H), 5.20(s, 1H), 4.80 (dd, J=3.7, 4.8 Hz, 1H), 3.95 (s, 3H), 2.97-3.03 (m, 1H),2.75-2.82 (m, 1H), 2.57-2.64 (m, 2H), 2.52-2.57 (m, 2H), 2.45-2.52 (m,3H), 2.35-2.42 (m, 1H), 2.04 (t, J=2.57 Hz, 1H), 2.01-2.09 (m, 1H); ¹³CNMR (150 MHz, CDCl₃) δ178.7, 171.4, 171.0, 168.9, 99.3, 98.9, 94.5,82.9, 69.9, 59.5, 57.9, 52.1, 51.3, 48.9, 35.6, 31.0, 26.3, 15.2; ESI-MSm/z: 562.9 [M+Na]⁺; ESI-HRMS: m/z calcd for C₁₈H₂₀N₂O₄Na³⁵Cl₅ ³⁷Cl[M+Na]⁺, 562.9422; found, 562.9427.

Example 13 Preparation of 1-5C

Under a similar procedure described in Example 4, 1-5c (2.4 mg, 0.0044mmol) was prepared from 1-4c (6 mg, 0.013 mmol) and pivaloyl chloride asa colourless oil in a yield of 34%. The crude residue was purified bysilica gel flash chromatography eluting with hexanes/EtOAc (5:1→5:2).[α]²⁰ _(D)+24.2° (c 0.33, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ6.51 (d,J=7.9 Hz, 1H), 5.75 (dt, J=3.5, 8.3 Hz, 1H), 5.19 (s, 1H), 4.78-4.80 (m,1H), 3.94 (s, 3H), 2.97 (ddd, J=4.7, 11.7, 14.4 Hz, 1H), 2.72 (ddd,J=3.4, 11.7, 14.7 Hz, 1H), 2.57-2.63 (m, 1H), 2.53-2.56 (m, 2H), 2.47(tt, J=4.1, 12.6 Hz, 1H), 2.34-2.41 (m, 1H), 2.01-2.08 (m, 1H), 1.25 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ178.8, 178.6, 171.8, 168.9, 99.4, 98.9,94.5, 59.5, 57.9, 51.9, 51.4, 48.9, 39.1, 31.0, 27.7, 26.3; ESI-MS m/z:567.0 [M+Na]⁺; ESI-HRMS: m/z calcd for C₁₈H₂₄N₂O₄NaCl₆ [M+Na]⁺,564.9765; found, 564.9764.

Example 14 Preparation of 1-6D

1-6d (1.3 mg, 0.0023 mmol) was prepared from 1-4d (5 mg, 0.0108 mmol)and ethanesulfonyl chloride as a colourless oil in a yield of 21%. Thecrude residue was purified by silica gel flash chromatography elutingwith hexanes/EtOAc (25:2→5:1). [α]²⁰ _(D)+14.2° (c 0.21, CHCl₃); ¹H NMR(600 MHz, CDCl₃) δ5.22-5.24 (m, 1H), 5.21 (s, 1H), 5.15-5.20 (m, J=2.8,9.5 Hz, 1H), 4.78 (dd, J=3.0, 5.5 Hz, 1H), 3.96 (s, 3H), 3.00-3.07 (m,2H), 2.92-3.00 (m, 2H), 2.74-2.81 (m, 1H), 2.65-2.71 (m, 1H), 2.44-2.50(m, 1H), 2.35-2.42 (m, 1H), 2.26-2.32 (m, 1H), 1.87-1.95 (m, 1H), 1.39(t, J=7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ179.0, 171.7, 169.6, 99.1,99.0, 94.6, 59.6, 58.5, 55.7, 51.6, 48.4, 48.0, 30.6, 26.1, 8.4; ESI-MSm/z: 574.9 [M+Na]⁺; ESI-HRMS: m/z calcd for C₁₅H₂₀N₂O₅NaSCl₆ [M+Na]⁺,572.9122; found, 572.9114.

Example 15 Preparation of 1-6C

1-6c (1.2 mg, 0.0021 mmol) was prepared from 1-4c (5 mg, 0.013 mmol) andethanesulfonyl chloride as a colourless oil in a yield of 20%. The cruderesidue was purified by silica gel flash chromatography eluting withhexanes/EtOAc (5:1→5:2). [α]²⁰ _(D)−13.8° (c 0.36, CHCl₃); ¹H NMR (600MHz, CDCl₃) δ5.31 (br. s., 1H), 5.23 (s, 1H), 4.85-4.89 (m, 1H), 3.98(s, 3H), 3.01-3.10 (m, 2H), 2.92-3.00 (m, 2H), 2.59-2.65 (m, 1H), 2.57(dd, J=5.3, 10.0 Hz, 2H), 2.40-2.44 (m, 1H), 2.35-2.40 (m, J=4.1 Hz,1H), 2.07 (br. s., 1H), 1.41 (t, J=7.3 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃)δ179.0, 171.5, 169.2, 99.0, 98.9, 94.4, 59.6, 58.0, 56.0, 51.3, 48.9,48.1, 31.5, 26.2, 8.4; ESI-MS m/z: 574.9 [M+Na]⁺; ESI-HRMS: m/z calcdfor C₁₅H₂₀N₂O₅NaS³⁵Cl₅ ³⁷Cl [M+Na]⁺, 574.9092; found, 574.9084.

Example 16 In Vitro Activity of Exemplary Compounds

LNCaP (2.4×10⁴ cell/well) cells were seeded on 24-well plates overnightbefore transfection with PSA(6.1 kb)-luciferase plasmid (0.25 ug/well)in serum-free, red phenol-free media. The next day, cells werepre-treated with compounds of the invention for 1 hour before theaddition of synthetic androgen, R1881 (1 nM) to transactivate androgenreceptor (AR) . After 48 h of incubation with R1881, the cells wereharvested, and relative luciferase activity was determined as a read-outfor androgen receptor (AR) transcriptional activity relative to acontrol. Test compounds were added to the cells at variousconcentrations and activity for each treatment was normalized to thepredicted maximal activity induction (in the absence of test compounds,vehicle only). Transfection experiments were performed using triplicatewells.

Compounds 1-1a, 1-1b, 1-1c, 1-1d, 1-2c, 1-2d, 1-3c, 1-3d, 1-4c, 1-4d,1-5c, 1-6d, 1-7c, 1-7d, 1-8c, 1-8d and 1-9c were each tested accordingto the above procedures. Each of the tested compounds, with theexception of 1-8d, showed a decrease in luciferase activity relative tothe control (i.e., compounds had activity as inhibitors of ARtranscriptional activity). Compound 1-8d showed a slight increase inluciferase activity relative to the control, which can possibly beexplained by the variability in assay reproducibility.

Data comparing activity of exemplary compounds to Sintokamide A andSintokamide B (“Sint A and Sint B, respectively) is provided in FIGS.1-3.

Furthermore, toxicity is assessed by both microscopic examination andreduction of protein levels. Solubility is assessed both macroscopically(cloudy media) and microscopically (formation of granules or crystals).

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet, areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments. These and other changes can be made to the embodiments inlight of the above-detailed description. In general, in the followingclaims, the terms used should not be construed to limit the claims tothe specific embodiments disclosed in the specification and the claims,but should be construed to include all possible embodiments along withthe full scope of equivalents to which such claims are entitled.Accordingly, the claims are not limited by the disclosure.

We claim:
 1. A compound having the following structure (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein: Y¹ and Y² are each independently O or S; R¹ is H, C₁-C₆ alkylor C₁-C₆ haloalkyl; R² is H, —C(═O)R⁷ or —S(O)_(n)R⁸; R³ and R⁴ arestraight-chain C₁-C₆ haloalkyl; R⁵ and R⁶ are each independently H, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy; R⁷ isC₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy; R⁸ isC₁-C₆ alkyl or C₁-C₆ haloalkyl;

is a carbon-carbon double bond or a carbon-carbon single bond, such thatall valences are satisfied; and n is 0, 1 or
 2. 2. The compound of claim1, wherein the compound has the following structure (Ia):


3. The compound of claim 1, wherein Y¹ is O.
 4. The compound of claim 1,wherein Y² is O.
 5. The compound of claim 1, wherein R¹ is H.
 6. Thecompound of claim 1, wherein R² is H.
 7. The compound of claim 1,wherein R² is —C(═O)R⁷.
 8. The compound of claim 7, wherein R⁷ is C₁-C₆alkyl.
 9. The compound of claim 8, wherein R⁷ is ethyl, t-butyl or


10. The compound of claim 7, wherein R⁷ is C₁-C₆alkoxy.
 11. The compoundof claim 10, wherein R⁷ is t-butoxy.
 12. The compound of any one ofclaims 1-5, wherein R² is —S(O)_(n)R⁸.
 13. The compound of claim 12,wherein R⁸ is C₁-C₆ alkyl.
 14. The compound of claim 13, wherein R⁸ isethyl.
 15. The compound of claim 12, wherein n is
 2. 16. The compound ofclaim 1, wherein R⁵ is C₁-C₆ alkoxy.
 17. The compound of claim 16,wherein C₁-C₆ alkoxy is methoxy.
 18. The compound of claim 1, wherein R⁶is H.
 19. The compound of claim 1 , wherein at least one of R³ or R⁴ isa straight-chain C₁-C₆ chloroalkyl.
 20. The compound of claim 19,wherein C₁-C₆ chloroalkyl comprises a perchloro-substituted carbon. 21.The compound of claim 1, wherein R³ or R⁴, or both, is3,3,3-trichloropropyl.
 22. The compound of claim 1, wherein

is a carbon-carbon double bond.
 23. The compound of claim 1, wherein thecompound has one of the following structures:


24. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 25. A pharmaceutical compositioncomprising a compound of claim 1, an additional therapeutic agent and apharmaceutically acceptable carrier.
 26. A method for modulatingandrogen receptor (AR) activity, the method comprising administering thepharmaceutical composition of claim 24 to a subject in need thereof. 27.A method for modulating androgen receptor (AR) activity, the methodcomprising administering the compound of claim 1 and an additionaltherapeutic agent to a subject in need thereof.
 28. The compound ofclaim 1, wherein the compound has the following structure (Ib):


29. The compound of claim 1, wherein the compound has the followingstructure (Ic):


30. The compound of claim 1, wherein the compound has the followingstructure (Id):